Tricyclic sulphonamide compounds and methods of making and using same

ABSTRACT

The invention provides tricyclic compounds and their use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making various tricyclic compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application 61/722,449 filed Nov. 5, 2012, hereby incorporated by reference in its entirety.

BACKGROUND

Over 1.1 billion people worldwide are reported to be overweight. Obesity is estimated to affect over 90 million people in the United States alone. Twenty-five percent of the population in the United States over the age of twenty is considered clinically obese. While being overweight or obese presents problems (for example restriction of mobility, discomfort in tight spaces such as theater or airplane seats, social difficulties, etc.), these conditions, in particular clinical obesity, affect other aspects of health, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being overweight or obese. The estimated mortality from obesity-related conditions in the United States is over 300,000 annually (O'Brien et al. Amer J Surgery (2002) 184:4S-8S; and Hill et al. (1998) Science, 280:1371).

There is no curative treatment for being overweight or obese. Traditional pharmacotherapies for treating an overweight or obese subject, such as serotonin and noradrenergic re-uptake inhibitors, noradrenergic re-uptake inhibitors, selective serotonin re-uptake inhibitors, intestinal lipase inhibitors, or surgeries such as stomach stapling or gastric banding, have been shown to provide minimal short-term benefits or significant rates of relapse, and have further shown harmful side-effects to patients.

MetAP2 encodes a protein that functions at least in part by enzymatically removing the amino terminal methionine residue from certain newly translated proteins such as glyceraldehyde-3-phosphate dehydrogenase (Warder et al. (2008) J Proteome Res 7:4807). Increased expression of the MetAP2 gene has been historically associated with various forms of cancer. Molecules inhibiting the enzymatic activity of MetAP2 have been identified and have been explored for their utility in the treatment of various tumor types (Wang et al. (2003) Cancer Res. 63:7861) and infectious diseases such as microsporidiosis, leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed. Sci. 9:34). Notably, inhibition of MetAP2 activity in obese and obese-diabetic animals leads to a reduction in body weight in part by increasing the oxidation of fat and in part by reducing the consumption of food (Rupnick et al. (2002) Proc. Natl. Acad. Sci. USA 99:10730).

Such MetAP2 inhibitors may be useful as well for patients with excess adiposity and conditions related to adiposity including type 2 diabetes, hepatic steatosis, and cardiovascular disease (via e.g. ameliorating insulin resistance, reducing hepatic lipid content, and reducing cardiac workload). Accordingly, compounds capable of modulating MetAP2 are needed to address the treatment of obesity and related diseases as well as other ailments favorably responsive to MetAP2 modulator treatment.

SUMMARY

The invention provides, for example, compounds which may be modulators of MetAP2, and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions containing them as an active ingredient both alone or in combination with other agents, as well as provides for their use as medicaments and/or in the manufacture of medicaments for the inhibition of MetAP2 activity in warm-blooded animals such as humans. In particular this invention relates to compounds useful for the treatment of obesity, type 2 diabetes, and other obesity-associated conditions. Also provided are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

The features and other details of the disclosure will now be more particularly described. Before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

Definitions

“Treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C₂₋₆alkenyl, and C₃₋₄alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O—). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C₁₋₆alkoxy, and C₂₋₆alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

The term “alkoxyalkyl” as used herein refers to a straight or branched alkyl group attached to oxygen, attached to a second straight or branched alkyl group (alkyl-O-alkyl-). Exemplary alkoxyalkyl groups include, but are not limited to, alkoxyalkyl groups in which each of the alkyl groups independently contains 1-6 carbon atoms, referred to herein as C₁₋₆alkoxy-C₁₋₆alkyl. Exemplary alkoxyalkyl groups include, but are not limited to methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl etc.

The term “alkyoxycarbonyl” as used herein refers to a straight or branched alkyl group attached to oxygen, attached to a carbonyl group (alkyl-O—C(O)—). Exemplary alkoxycarbonyl groups include, but are not limited to, alkoxycarbonyl groups of 1-6 carbon atoms, referred to herein as C₁₋₆alkoxycarbonyl. Exemplary alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.

The term “alkenyloxy” used herein refers to a straight or branched alkenyl group attached to oxygen (alkenyl-O—). Exemplary alkenyloxy groups include, but are not limited to, groups with an alkenyl group of 3-6 carbon atoms, referred to herein as C₃₋₆alkenyloxy. Exemplary “alkenyloxy” groups include, but are not limited to allyloxy, butenyloxy, etc.

The term “alkynyloxy” used herein refers to a straight or branched alkynyl group attached to oxygen (alkynyl-O). Exemplary alkynyloxy groups include, but are not limited to, groups with an alkynyl group of 3-6 carbon atoms, referred to herein as C₃₋₆alkynyloxy. Exemplary alkynyloxy groups include, but are not limited to, propynyloxy, butynyloxy, etc.

The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C₁₋₆alkyl, C₁₋₄alkyl, and C₁₋₃alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

The term “alkylcarbonyl” as used herein refers to a straight or branched alkyl group attached to a carbonyl group (alkyl-C(O)—). Exemplary alkylcarbonyl groups include, but are not limited to, alkylcarbonyl groups of 1-6 atoms, referred to herein as C₁₋₆alkylcarbonyl groups. Exemplary alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, etc.

The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C₂₋₆alkynyl, and C₃₋₆alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “cyano” as used herein refers to the radical —CN.

The term “cycloalkoxy” as used herein refers to a cycloalkyl group attached to oxygen (cycloalkyl-O—). Exemplary cycloalkoxy groups include, but are not limited to, cycloalkoxy groups of 3-6 carbon atoms, referred to herein as C₃₋₆cycloalkoxy groups. Exemplary cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclohexyloxy, etc

The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C₃₋₆cycloalkyl or C₄₋₆cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The terms “heteroaryl” or “heteroaromatic group” as used herein refers to a monocyclic aromatic 5-6 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine etc.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated, 4-10 membered ring structures, including bridged or fused rings, and whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc.

The term “heterocyclyloxy” as used herein refers to a heterocyclyl group attached to oxygen (heterocyclyl-O—).

The term “heteroaryloxy” as used herein refers to a heteroaryl group attached to oxygen (heteroaryl-O—).

The terms “hydroxy” and “hydroxyl” as used herein refers to the radical —OH.

The term “oxo” as used herein refers to the radical ═O.

“Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

“Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the invention can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The mammal treated in the methods of the invention is desirably a mammal in which treatment of obesity or weight loss is desired. “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.

In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g. mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the invention are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in weight loss.

The term “pharmaceutically acceptable salt(s)” as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(−),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol

denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”

Individual enantiomers and diasteriomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

The invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. For example, a compound of the invention may have one or more H atom replaced with deuterium.

Certain isotopically-labeled disclosed compounds (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C₁₋₈)alkyl, (C₂₋₁₂)alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—(C₁₋₂)alkylamino(C₂₋₃)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C₁₋₂)alkyl, N,N-di(C₁₋₂)alkylcarbamoyl-(C₁₋₂)alkyl and piperidino-, pyrrolidino- or morpholino(C₂₋₃)alkyl.

Similarly, if a compound of the invention contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C₁₋₆)alkylcarbonyloxymethyl, 1-((C₁₋₆)alkylcarbonyloxy)ethyl, 1-methyl-1-((C₁₋₆)alkylcarbonyloxy)ethyl (C₁₋₆)alkoxycarbonyloxymethyl, N—(C₁₋₆)alkoxycarbonylaminomethyl, succinoyl, (C₁₋₆)alkylcarbonyl, α-amino(C₁₋₄)alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl, or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl, where each α-aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a compound of the invention incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio, et al., Molecules 2008, 13, 519 and references therein.

I. Tricyclic Compounds

In certain embodiments, the present invention provides compounds of Formula I or Formula II:

wherein

-   -   B¹ may be a 3-6 membered saturated or partially unsaturated         heterocyclic or carbocyclic ring;     -   B² may be a 3-6 membered saturated heterocyclic or carbocyclic         ring;     -   wherein the ring B¹ or B² may optionally be substituted by one         or more fluorine atoms on any of the available carbon atoms     -   D¹ may be a 5-7 membered heterocyclic, carbocyclic,         heteroaromatic or aromatic ring;     -   D² may be a 5-7 membered heterocyclic or carbocyclic ring;     -   wherein B¹ is fused to D¹ such that the two atoms shared by B¹         and D¹ are both carbon and B² is fused to D² such that the two         atoms shared by B² and D² are both carbon; and wherein for         Formula I the bond common to both the B¹ and D¹ rings may be a         single or double bond;     -   X¹ may be selected from the group consisting of:         ⁺—C(R^(D1)R^(D2))—*, ⁺—W¹—*,         ⁺—C(R^(D1)R^(D2))—C(R^(D5)R^(D6))—*, ⁺—C(R^(C1))═C(R^(C2))—*,         ⁺—W²—C(R^(D5)R^(D6))—*, ⁺—W²—C(O)—*, ⁺—C(R^(D1)R^(D2))—W⁴—*,         ⁺—N═C(R^(C2))—*, ⁺—C(R^(C1))═N—*,         ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,         ⁺—W²—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,         ⁺—W²—C(O)—C(R^(D5)R^(D6))—*,         ⁺—C(R^(D1)R^(D2))—W³—C(R^(D5)R^(D6))—*,         ⁺—C(R^(D1)R^(D2))—W³—C(O)—*,         ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—W⁴—* and         ⁺—C(R^(D1)R^(D2))—C(O)—W⁴—*; wherein the ⁺ and * indicate the         attachment points of X¹ as indicated in Formula I;     -   X² may be selected from the group consisting of:         ⁺—C(R^(D1)R^(D2))—*, ⁺—W¹—*,         ⁺—C(R^(D1)R^(D2))—C(R^(D5)R^(D6))—*, ⁺—W²—C(R^(D5)R^(D6))—*,         ⁺—W²—C(O)— *, ⁺—C(R^(D1)R^(D2))—W⁴—*,         ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,         ⁺—W²—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,         ⁺—W²—C(O)—C(R^(D5)R^(D6))—*,         ⁺—C(R^(D1)R^(D2))—W³—C(R^(D5)R^(D6))—*,         ⁺—C(R^(D1)R^(D2))—W³—C(O)—*,         ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—W⁴—* and         ⁺—C(R^(D1)R^(D2))—C(O)—W⁴—*; wherein the ⁺ and * indicate the         attachment points of X² as indicated in Formula II;     -   Y may be selected from the group consisting of: a bond,         *—CH₂—^(#), *—O—^(#), *—CH₂—CH₂—^(#), *—O—CH₂—^(#),         *—CH₂—O—^(#), *—CH₂—CH₂—CH₂—^(#), *—O—CH₂—CH₂—^(#) and         *—CH₂—O—CH₂—^(#); wherein the * and ^(#) indicate the attachment         points of Y as indicated in Formula I or Formula II;     -   W¹ may be selected from the group consisting of O, S, or         N(R^(N1));     -   W² may be selected from the group consisting of O or N(R^(N2));     -   W³ may be selected from the group consisting of O or N(R^(N3));     -   W⁴ may be selected from the group consisting of O or N(R^(N4));     -   A may be a ring selected from the group consisting of phenyl, a         5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each         selected from S, N or O, and a 4-7 membered heterocycle having         1, 2 or 3 heteroatoms each selected from N or O;     -   R^(B1) and R^(B2) are independently selected from the group         consisting of H, F, OH, CN, C₁₋₂alkoxy or C₁₋₃alkyl; wherein         C₁₋₃alkyl and C₁₋₂alkoxy are optionally substituted by a group         selected from OH, C₁₋₂alkoxy, CN or one or more fluorine atoms;     -   R^(A1) may be selected, independently for each occurrence, from         the group consisting of hydrogen, hydroxyl, cyano, halogen,         C₁₋₄alkyl or C₁₋₃alkoxy; wherein C₁₋₄alkyl, or C₁₋₃alkoxy may be         optionally substituted by one or more fluorines;     -   n may be 1 or 2;     -   R^(A2) may be selected from the group consisting of hydrogen,         R^(i)R^(j)N—, heterocyclyl, heterocyclyloxy and         heterocyclyl-(NR^(a))—; wherein said heterocyclyl may optionally         be substituted by one or more substituents selected from R^(g)         and wherein if said heterocyclyl contains a —NH moiety that         nitrogen may optionally be substituted by one or more groups         R^(h); or     -   R^(A2) may be selected from the group consisting of: C₁₋₆alkyl,         C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,         C₃₋₆alkenyloxy, C₃₋₆alkynyloxy, C₃₋₆cycloalkoxy,         C₁₋₆alkyl-S(O)_(w)— (wherein w is 0, 1 or 2),         C₁₋₆alkyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))-carbonyl-,         C₁₋₆alkylcarbonyl-N(R^(a))—,         C₁₋₆alkyl-N(R^(a))-carbonyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))—SO₂—,         C₁₋₆alkyl-SO₂—N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))—,         C₁₋₆alkylcarbonyl-N(R^(a))—C₁₋₆alkyl-,         C₁₋₆alkyl-N(R^(a))-carbonyl-C₁₋₆alkyl-, C₁₋₆alkoxyC₁₋₆alkyl-;         wherein C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,         C₁₋₆alkoxy, C₃₋₆alkenyloxy, C₃₋₆alkynyloxy, C₃₋₆cycloalkoxy,         C₁₋₆alkyl-S(O)_(w)—, C₁₋₆alkyl-N(R^(a))—,         C₁₋₆alkyl-N(R^(a))-carbonyl-, C₁₋₆alkylcarbonyl-N(R^(a))—,         C₁₋₆alkyl-N(R^(a))-carbonyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))—SO₂—,         C₁₋₆alkyl-SO₂—N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))—,         C₁₋₆alkylcarbonyl-N(R^(a))C₁₋₆alkyl-,         C₁₋₆alkyl-N(R^(a))-carbonyl-C₁₋₆alkyl-, C₁₋₆alkoxy-C₁₋₆alkyl may         optionally be substituted by R^(P), phenyl, phenoxy, heteroaryl,         heteroaryloxy, heteroaryl-(NR^(a))—, heterocyclyl,         heterocyclyloxy or heterocyclyl-N(R^(a))—; and wherein said         heteroaryl or phenyl may optionally be substituted with one or         more substituents selected from R^(f); and wherein said         heterocyclyl may optionally be substituted by one or more         substituents selected from R^(g); and wherein if said         heterocyclyl contains a —NH moiety that nitrogen may optionally         be substituted by one or more groups R^(h);     -   R^(D1) and R^(D2) may be each independently selected from the         group consisting of hydrogen, fluorine, hydroxyl, C₁₋₂alkyl or         C₁₋₂alkoxy; wherein the C₁₋₂alkyl and C₁₋₂alkoxy may optionally         be substituted by one or more fluorine atoms or a group selected         from cyano or hydroxyl;     -   R^(D3) and R^(D4) may be each independently selected from the         group consisting of hydrogen, fluorine, hydroxyl, cyano,         C₁₋₃alkyl or C₁₋₃alkoxy; wherein the C₁₋₃ alkyl and C₁₋₃ alkoxy         may optionally be substituted by one or more fluorine atoms or a         group selected from cyano, hydroxyl or N(R^(a)R^(b));     -   R^(D5) and R^(D6) may be each independently selected from the         group consisting of hydrogen, fluorine, hydroxyl, cyano,         C₁₋₂alkyl or C₁₋₂alkoxy; wherein the C₁₋₂alkyl and C₁₋₂alkoxy         may optionally be substituted by one or more fluorine atoms or a         group selected from cyano, hydroxyl or N(R^(a)R^(b));     -   R^(C1) may be selected from the group consisting of hydrogen,         halogen, C₁₋₂alkyl or C₁₋₂alkoxy; wherein the C₁₋₂alkyl or         C₁₋₂alkoxy may optionally be substituted by one or more fluorine         atoms;     -   R^(C2) may be selected from the group consisting of hydrogen,         halogen, hydroxyl, cyano, C₁₋₂alkyl or C₁₋₂alkoxy; wherein the         C₁₋₂alkyl and C₁₋₂alkoxy may optionally be substituted by one or         more fluorine atoms or a group selected from cyano, hydroxyl or         N(R^(a)R^(b));     -   R^(N1) may be selected from the group consisting of hydrogen or         C₁₋₂alkyl;     -   R^(N2) may be selected from the group consisting of hydrogen or         C₁₋₂alkyl;     -   R^(N3) may be selected from the group consisting of hydrogen,         C₁₋₃alkyl or C₁₋₂alkylcarbonyl; wherein the C₁₋₃alkyl and         C₁₋₂alkylcarbonyl may optionally be substituted by one or more         fluorine atoms or a group selected from cyano, hydroxyl or         N(R^(a)R^(b));     -   R^(N4) may be selected from the group consisting of hydrogen,         C₁₋₃alkyl or C₁₋₂alkylcarbonyl; wherein the C₁₋₃alkyl and         C₁₋₂alkylcarbonyl may optionally be substituted by one or more         fluorine atoms or a group selected from cyano, hydroxyl or         N(R^(a)R^(b));     -   R^(a) and R^(b) may be independently selected, for each         occurrence, from the group consisting of hydrogen and C₁₋₃alkyl;         wherein C₁₋₃alkyl may optionally be substituted by one or more         substituents selected from fluorine, cyano, oxo and hydroxyl;     -   or R^(a) and R^(b), together with the nitrogen to which they are         attached, may form a 4-6 membered heterocyclic ring, which may         have an additional heteroatom selected from O, S, or N; wherein         the 4-6 membered heterocyclic ring may optionally be substituted         by one or more substituents selected from the group consisting         of fluorine, cyano, oxo or hydroxyl;     -   R^(f) may be independently selected, for each occurrence, from         the group consisting of R^(P), hydrogen, C₁₋₆alkyl,         C₃₋₆cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,         C₁₋₆alkyl-S(O)_(w)—, (wherein w is 0, 1 or 2),         C₁₋₆alkylcarbonyl-N(R^(a))— and C₁₋₆alkoxycarbonyl-N(R^(a))—;         wherein C₁₋₆alkyl, C₃₋₆cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,         C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(w)—, C₁₋₆alkylcarbonyl-N(R^(a))—,         C₁₋₆alkoxycarbonyl-N(R^(a))— may be optionally substituted by         one or more substituents selected from R^(P);     -   R^(g) may be independently selected for each occurrence from the         group consisting of R^(P), hydrogen, oxo, C₁₋₆alkyl,         C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,         C₁₋₆alkyl-S(O)_(w)—, (wherein w is 0, 1 or 2),         C₁₋₆alkylcarbonyl-N(R^(a))— and C₁₋₆alkoxycarbonyl-N(R^(a))—;         wherein C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,         C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(w)—, C₁₋₆alkylcarbonyl-N(R^(a))—,         C₁₋₆alkoxycarbonyl-N(R^(a))— may be optionally substituted by         one or more substituents selected from R^(P);     -   R^(h) may be independently selected for each occurrence from the         group consisting of hydrogen, C₁₋₆alkyl, C₃₋₆alkenyl,         C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,         C₁₋₆alkoxycarbonyl-, R^(i)R^(j)N-carbonyl- and R^(i)R^(j)N—SO₂—;         wherein C₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl C₃₋₆ cycloalkyl and         C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl- may optionally be         substituted by one or more substituents selected from R^(P);     -   R^(i) and R^(j) may be selected independently for each         occurrence from the group consisting of hydrogen, C₁₋₄alkyl         C₃₋₆cycloalkyl, heterocyclyl and heterocyclylcarbonyl; wherein         C₁₋₄alkyl and C₃₋₆cycloalkyl may be optionally substituted by         one or more substituents selected from fluorine, hydroxyl,         cyano, R^(a)R^(b)N—, R^(a)R^(b)N-carbonyl- and C₁₋₃alkoxy and         wherein heterocyclyl and heterocyclylcarbonyl may be optionally         substituted by one or more substituents selected from C₁₋₆alkyl,         C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,         halo-C₁₋₆-alkyl, hydroxyl-C₁₋₆-alkyl, R^(a)R^(b)N—C₁₋₆alkyl- and         C₁₋₆-alkoxy-C₁₋₆-alkyl group; and wherein if said heterocyclyl         or heterocyclylcarbonyl contains a —NH moiety that nitrogen may         optionally be substituted by one or more groups C₁₋₆alkyl,         C₃₋₆alkenyl, C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂— and         C₁₋₆-alkylcarbonyl;     -   or R^(i) and R^(j) taken together with the nitrogen to which         they are attached may form a 4-7 membered heterocyclic ring,         which may have an additional heteroatom selected from O, S, or         N; wherein the 4-7 membered heterocyclic ring may be optionally         substituted on carbon by one or more substituents selected from         the group consisting of fluorine, hydroxyl, oxo, cyano,         C₁₋₆alkyl, C₁₋₆alkoxy, R^(a)R^(b)N—, R^(a)R^(b)N—SO₂— and         R^(a)R^(b)N-carbonyl-; wherein said C₁₋₆alkyl or C₁₋₆alkoxy may         optionally be substituted by fluorine, hydroxyl or cyano; and         wherein the 4-7 membered heterocyclic ring may be optionally         substituted on nitrogen by one or more substituents selected         from the group consisting of C₁₋₆alkyl and         R^(a)R^(b)N-carbonyl-; and wherein said C₁₋₆alkyl may be         optionally substituted by fluorine, hydroxyl, cyano;     -   R^(P) may be independently selected, for each occurrence, from         the group consisting of halogen, hydroxyl, cyano, C₁₋₆alkoxy,         R^(i)R^(j)N—, R^(i)R^(j)N-carbonyl-, R^(i)R^(j)N—SO₂— and         R^(i)R^(j)N-carbonyl-N(R^(a))—;         and pharmaceutically acceptable salts, stereoisomers, esters and         prodrugs thereof.

In some embodiments, X¹ may be selected from the group consisting of: ⁺—O—*, ⁺—N(R^(N1))—*, ⁺—C(R^(D1)R^(D2))—C(R^(D5)R^(D6))—*, ⁺—C(R^(C1))═C(R^(C2))—*, ⁺—O—C(R^(D5)R^(D6))—*, ⁺—N(R^(N2))—C(R^(D5)R^(D6))—*, ⁺—O—C(O)—*, ⁺—N(R^(N2))—C(O)—*, ⁺—N═C(R^(C2))—* and ⁺—O—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*; wherein the ⁺ and * indicate the attachment points of X¹ as indicated in Formula I. Exemplary X¹ moities may be selected from the group consisting of: ⁺—NH—*, ⁺—O—CH₂—*, ⁺—NH—CH₂—*, ⁺—N═CH—* and ⁺—CH═CH—*; wherein the ⁺ and * indicate the attachment points of X¹ as indicated in Formula I.

In some embodiments X² may be selected from the group consisting of ⁺—O—*, ⁺—N(R^(N1))—*, ⁺—C(R^(D1)R^(D2))—C(R^(D5)R^(D6))—*, ⁺—O—C(R^(D5)R^(D6))—*, ⁺—N(R^(N2))—C(R^(D5)R^(D6))—*, ⁺—O—C(O)—*, ⁺—N(R^(N2))—C(O)—*, and ⁺—O—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*; wherein the ⁺ and * indicate the attachment points of X² as indicated in Formula II. Exemplary X² moities may be selected from the group consisting of: ⁺—O—CH₂—* and ⁺—NH—CH₂—*; wherein the ⁺ and * indicate the attachment points of X² as indicated in Formula II.

In one embodiment, R^(D1), R^(D2), R^(C1), R^(N1) and R^(N2) may be independently selected for each occurrence from the group consisting of hydrogen and methyl. For example, R^(D1), R^(D2), R^(C1), R^(N1) and R^(N2) may be hydrogen.

In certain embodiments, R^(D3), R^(D4), R^(D5) and R^(D6) may be independently selected for each occurrence from the group consisting of hydrogen, fluorine, cyano and C₁₋₂alkyl. For example, R^(D3), R^(D4), R^(D5) and R^(D6) may be hydrogen.

In an embodiment, R^(C2) may be selected from the group consisting of hydrogen, halogen, cyano and C₁₋₂alkyl. For example, R^(C2) may be hydrogen.

In certain embodiments, R^(B1) of the tricyclic compound of Formula II may be selected from the group consisting of H, F or C₁₋₂alkyl. For example, R^(B1) may be H or methyl.

In another embodiment, R^(B2) of the tricyclic compound of Formula II may be hydrogen.

In certain embodiments, ring D¹ may be selected from the group consisting of:

wherein the *, # and + indicate the points of attachment to the phenyl ring and the B¹ ring as indicated in Formula I. Exemplary D¹ rings that may form part of the contemplated tricyclic core may include those selected from the group consisting of:

In certain embodiments, ring D² may be selected from the group consisting of:

wherein the *, # and + indicate the points of attachment to the phenyl ring and the B² ring as indicated in Formula II.

In some embodiments, Y may be selected from the group consisting of a bond, *—O—CH₂ ^(#) and *—CH₂—O—CH₂—^(#); wherein the * and # indicate the points of attachment to Y as indicated in Formula I or Formula II. For example, Y may be a bond or *—O—CH₂ ^(#); wherein the * and # indicate the points of attachment to Y as indicated in Formula I or Formula II.

For example, ring B¹ or B² may, in certain embodiments, be selected from the group consisting of:

wherein the * and # indicate the points of attachment to Y as indicated in Formula I and II. Exemplary B¹ and B² rings that may form part of the contemplated tricyclic core may include those selected from the group consisting of:

Also provided herein is a compound represented by Formula IV:

-   -   D² may be a 5-7 membered partially unsaturated heterocyclic or         carbocyclic ring;     -   X² may be selected from the group consisting of:         ⁺—C(R^(D1)R^(D2))—*, ⁺—W¹—*,         ⁺—C(R^(D1)R^(D2))—C(R^(D5)R^(D6))—*, ⁺—W²—C(R^(D5)R^(D6))—*,         ⁺—W²—C(O)—*, ⁺—C(R^(D1)R^(D2))—W⁴—*,         ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,         ⁺—W²—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,         ⁺—W²—C(O)—C(R^(D5)R^(D6))—*,         ⁺—C(R^(D1)R^(D2))—W³—C(R^(D5)R^(D6))—*,         ⁺—C(R^(D1)R^(D2))—W³—C(O)—*,         ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—W⁴—* and         ⁺—C(R^(D1)R^(D2))—C(O)—W⁴—*; wherein the ⁺ and * indicate the         attachment points of X² as indicated in Formula IV;     -   W¹ may be selected from the group consisting of O, S or         N(R^(N1));     -   W² may be selected from the group consisting of O or N(R^(N2));     -   W³ may be selected from the group consisting of O or N(R^(N3));     -   W⁴ may be selected from the group consisting of O or N(R^(N4));     -   R^(B1) may be selected from the group consisting of H, F, OH,         CN, C₁₋₂alkoxy or C₁₋₃alkyl; wherein C₁₋₃alkyl and C₁₋₂alkoxy         are optionally substituted by a group selected from OH,         C₁₋₂alkoxy, CN or one or more fluorine atoms;     -   R^(A1) may be selected, independently for each occurrence, from         the group consisting of hydrogen, hydroxyl, cyano, halogen,         C₁₋₄alkyl or C₁₋₃alkoxy; wherein C₁₋₄alkyl, or C₁₋₃alkoxy may be         optionally substituted by one or more fluorines;     -   n may be 0, 1, or 2;     -   R^(A2) may be selected from the group consisting of hydrogen,         R^(i)R^(j)N—, heterocyclyl, heterocyclyloxy and         heterocyclyl-(NR^(a))—; wherein said heterocyclyl may optionally         be substituted by one or more substituents selected from R^(g)         and wherein if said heterocyclyl contains a —NH moiety that         nitrogen may optionally be substituted by one or more groups         R^(h); or     -   R^(A2) may be selected from the group consisting of: C₁₋₆alkyl,         C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,         C₃₋₆alkenyloxy, C₃₋₆alkynyloxy, C₃₋₆cycloalkoxy,         C₁₋₆alkyl-S(O)_(w)— (wherein w is 0, 1 or 2),         C₁₋₆alkyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))-carbonyl-,         C₁₋₆alkylcarbonyl-N(R^(a))—,         C₁₋₆alkyl-N(R^(a))-carbonyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))—SO₂—,         C₁₋₆alkyl-SO₂—N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))—,         C₁₋₆alkylcarbonyl-N(R^(a))—C₁₋₆alkyl-,         C₁₋₆alkyl-N(R^(a))-carbonyl-C₁₋₆alkyl-, C₁₋₆alkoxyC₁₋₆alkyl-;         wherein C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,         C₁₋₆alkoxy, C₃₋₆alkenyloxy, C₃₋₆alkynyloxy, C₃₋₆cycloalkoxy,         C₁₋₆alkyl-S(O)_(w)—, C₁₋₆alkyl-N(R^(a))—,         C₁₋₆alkyl-N(R^(a))-carbonyl-, C₁₋₆alkylcarbonyl-N(R^(a))—,         C₁₋₆alkyl-N(R^(a))-carbonyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))—SO₂—,         C₁₋₆alkyl-SO₂—N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))—,         C₁₋₆alkylcarbonyl-N(R^(a))C₁₋₆alkyl-,         C₁₋₆alkyl-N(R^(a))-carbonyl-C₁₋₆alkyl-, C₁₋₆alkoxy-C₁₋₆alkyl may         optionally be substituted by R^(P), phenyl, phenoxy, heteroaryl,         heteroaryloxy, heteroaryl-(NR^(a))—, heterocyclyl,         heterocyclyloxy or heterocyclyl-N(R^(a))—; and wherein said         heteroaryl or phenyl may optionally be substituted with one or         more substituents selected from R^(f); and wherein said         heterocyclyl may optionally be substituted by one or more         substituents selected from R^(g); and wherein if said         heterocyclyl contains a —NH moiety that nitrogen may optionally         be substituted by one or more groups R^(h);     -   R^(D1) and R^(D2) may be each independently selected from the         group consisting of hydrogen, fluorine, hydroxyl, C₁₋₂alkyl or         C₁₋₂alkoxy; wherein the C₁₋₂alkyl and C₁₋₂alkoxy may optionally         be substituted by one or more fluorine atoms or a group selected         from cyano or hydroxyl;     -   R^(D3) and R^(D4) may be each independently selected from the         group consisting of hydrogen, fluorine, hydroxyl, cyano,         C₁₋₃alkyl or C₁₋₃alkoxy; wherein the C₁₋₃ alkyl and C₁₋₃ alkoxy         may optionally be substituted by one or more fluorine atoms or a         group selected from cyano, hydroxyl or N(R^(a)R^(b));     -   R^(D5) and R^(D6) may be each independently selected from the         group consisting of hydrogen, fluorine, hydroxyl, cyano,         C₁₋₂alkyl or C₁₋₂alkoxy; wherein the C₁₋₂alkyl and C₁₋₂alkoxy         may optionally be substituted by a substituent or substituents         selected from the group consisting of: one or more fluorine         atoms, cyano, hydroxyl or N(R^(a)R^(b));

R^(C1) may be selected from the group consisting of hydrogen, halogen, C₁₋₂alkyl or C₁₋₂alkoxy; wherein the C₁₋₂alkyl or C₁₋₂alkoxy may optionally be substituted by one or more fluorine atoms;

R^(C2) may be selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C₁₋₂alkyl or C₁₋₂alkoxy; wherein the C₁₋₂alkyl and C₁₋₂alkoxy may optionally be substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or N(R^(a)R^(b));

-   -   R^(N1) may be selected from the group consisting of hydrogen or         C₁₋₂alkyl;     -   R^(N2) may be selected from the group consisting of hydrogen or         C₁₋₂alkyl;     -   R^(N3) may be selected from the group consisting of hydrogen,         C₁₋₃alkyl or C₁₋₂alkylcarbonyl; wherein the C₁₋₃alkyl and         C₁₋₂alkylcarbonyl may optionally be substituted by a substituent         or substituents selected from the group consisting of: one or         more fluorines, cyano, hydroxyl or N(R^(a)R^(b));     -   R^(N4) may be selected from the group consisting of hydrogen,         C₁₋₃alkyl or C₁₋₂alkylcarbonyl; wherein the C₁₋₃alkyl and         C₁₋₂alkylcarbonyl may optionally be substituted by a substituent         or substituents selected from the group consisting of: one or         more fluorines, cyano, hydroxyl or N(R^(a)R^(b));     -   R^(a) and R^(b) may be independently selected, for each         occurrence, from the group consisting of hydrogen and C₁₋₃alkyl;         wherein C₁₋₃alkyl may optionally be substituted by one or more         substituents selected from fluorine, cyano, oxo and hydroxyl;     -   or R^(a) and R^(b), together with the nitrogen to which they are         attached, may form a 4-6 membered heterocyclic ring, which may         have an additional heteroatom selected from O, S, or N; wherein         the 4-6 membered heterocyclic ring may optionally be substituted         by one or more substituents selected from the group consisting         of fluorine, cyano, oxo or hydroxyl;     -   R^(f) may be independently selected, for each occurrence, from         the group consisting of R^(P), hydrogen, C₁₋₆alkyl,         C₃₋₆cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, (wherein w         is 0, 1 or 2), C₁₋₆alkylcarbonyl-N(R^(a))— and         C₁₋₆alkoxycarbonyl-N(R^(a))—; wherein C₁₋₆alkyl, C₃₋₆cycloalkyl,         C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,         C₁₋₆alkylcarbonyl-N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))— may be         optionally substituted by one or more substituents selected from         R^(P);     -   R^(g) may be independently selected for each occurrence from the         group consisting of R^(P), hydrogen, oxo, C₂₋₆alkenyl,         C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, (wherein w is 0, 1 or         2), C₁₋₆alkylcarbonyl-N(R^(a))— and         C₁₋₆alkoxycarbonyl-N(R^(a))—; wherein C₁₋₆alkyl, C₂₋₆alkenyl,         C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(w)—,         C₁₋₆alkylcarbonyl-N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))— may be         optionally substituted by one or more substituents selected from         R^(P);     -   R^(h) may be independently selected for each occurrence from the         group consisting of hydrogen, C₁₋₆alkyl, C₃₋₆alkenyl,         C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,         C₁₋₆alkoxycarbonyl-, R^(i)R^(j)N-carbonyl- and R^(i)R^(j)N—SO₂—;         wherein C₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl C₃₋₆cycloalkyl and         C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl- may optionally be         substituted by one or more substituents selected from R^(P);     -   R^(i) and R^(j) may be selected independently for each         occurrence from the group consisting of hydrogen, C₁₋₄alkyl         C₃₋₆cycloalkyl, heterocyclyl and heterocyclylcarbonyl; wherein         C₁₋₄alkyl and C₃₋₆cycloalkyl may be optionally substituted by         one or more substituents selected from fluorine, hydroxyl,         cyano, R^(a)R^(b)N—, R^(a)R^(b)N-carbonyl- and C₁₋₃alkoxy and         wherein heterocyclyl and heterocyclylcarbonyl may be optionally         substituted by one or more substituents selected from C₁₋₆alkyl,         C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,         halo-C₁₋₆-alkyl, hydroxyl-C₁₋₆ alkyl and C₁₋₆-alkoxy-C₁₋₆-alkyl         group; and wherein if said heterocyclyl or heterocyclylcarbonyl         contains a —NH moiety that nitrogen may optionally be         substituted by one or more groups C₁₋₆alkyl, C₃₋₆alkenyl,         C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂— and         C₁₋₆-alkylcarbonyl;     -   or R^(i) and R^(j) taken together with the nitrogen to which         they are attached may form a 4-7 membered heterocyclic ring,         which may have an additional heteroatom selected from O, S, or         N; wherein the 4-7 membered heterocyclic ring may be optionally         substituted on carbon by one or more substituents selected from         the group consisting of fluorine, hydroxyl, oxo, cyano,         C₁₋₆alkyl, C₁₋₆alkoxy, R^(a)R^(b)N—, R^(a)R^(b)N—SO₂— and         R^(a)R^(b)N-carbonyl-; wherein said C₁₋₆alkyl or C₁₋₆alkoxy may         optionally be substituted by fluorine, hydroxyl or cyano; and         wherein the 4-7 membered heterocyclic ring may be optionally         substituted on nitrogen by one or more substituents selected         from the group consisting of C₁₋₆alkyl and         R^(a)R^(b)N-carbonyl-; and wherein said C₁₋₆alkyl may be         optionally substituted by one or more substituents selected from         the group consisting of fluorine, hydroxyl, cyano;     -   R^(P) may be independently selected, for each occurrence, from         the group consisting of halogen, hydroxyl, cyano, C₁₋₆alkoxy,         R^(i)R^(j)N—, R^(i)R^(j)N-carbonyl-, R^(i)R^(j)N—SO₂— and         R^(i)R^(j)N-carbonyl-N(R^(a))—;     -   and pharmaceutically acceptable salts, stereoisomers, esters and         prodrugs thereof.

In certain embodiments, R^(A1) of the tricyclic compound of Formula IV may be hydrogen or fluorine.

In another embodiment, R^(A2) of the tricyclic compound of Formula IV may be selected from the group consisting of hydrogen, R^(i)R^(j)N, heterocyclyl, C₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, heterocyclyl-NR^(a)-carbonyl-C₁₋₆alkyl and heterocyclyl-carbonyl-NR^(a)—C₁₋₆alkyl; wherein said heterocyclyl may optionally be substituted by one or more groups R^(g); and wherein if said heterocyclyl contains a —NH moiety, that nitrogen may optionally be substituted by on or more groups R^(h); and wherein said C₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆cycloalkyl and C₁₋₆alkoxy may optionally be substituted by one or more groups R^(P).

Also provided herein are compounds that may be selected from the group consisting of (1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, or enantiomers thereof; (1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopro-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[4-fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)-pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((Z)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((E)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[(E)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[(Z)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, or enantiomers thereof; (1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(Z)-3-((S)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-(4-fluoro-2-[(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl]benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-(4-fluoro-2-[(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl]benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[(((S)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((3R)-1-ethylpyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)amino-methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid-formic acid (1:1); (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid-formic acid (1:1) and pharmaceutically acceptable salts, stereoisomers, esters and prodrugs thereof.

Procedures for making compounds described herein are provided below with reference to Schemes 1-3. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio or carboxyl groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds of Formula I, as disclosed herein, or as exemplified in, for example, General Formula I, below. Starting materials used in the following schemes can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

The general synthetic strategy used to prepare the tricyclic compounds of General Formula I is depicted in Scheme 1. The tricyclic system may be assembled in a variety of ways, starting from an appropriately substituted and protected phenyl ring 1A. The group G′ is a suitably protected carboxylic acid, such as a methyl- or t-butyl carboxylate or is a functional group that may be readily converted into a carboxylic acid, such as a nitrile or aldehyde. The group G is a sulfonamide group, or a functional group that may be subsequently converted into a sulfonamide group such as a suitably protected aniline. The B′-ring can be directly attached to the substituted phenyl ring to give intermediate 1B, and then the D′-ring can be formed by an intra-molecular reaction to give intermediate 1E. Alternatively, the B′-ring can be attached to the substituted phenyl ring 1A via a linker, X′, to give intermediate 1C, and then the D′-ring can be formed by an intra-molecular reaction to give intermediate 1E. Alternatively, the D′-ring can be built up onto the substituted phenyl ring to give intermediate 1D, and then the B′-ring assembled to give intermediate 1E. Modifications to the B′ and D′ rings may be necessary to provide the required saturated or partially unsaturated ring systems and this may be carried out prior to the formation of the tricyclic core or after it. For example, if the B′ ring is a dihydro- or tetrahydrofuran it may be prepared from a corresponding furan compound by hydrogenation in the presence of a metal catalyst (for example palladium or palladium hydroxide on a solid support such as carbon) in a solvent (such as ethyl acetate, ethanol or dioxane) optionally in the presence of an acid (such as acetic acid). The hydrogenation may be carried out at any stage during the synthesis of the compounds either before or after the formation of the tricyclic core. Compounds of Formula I can be prepared from intermediate 1E by removal of any protecting groups. Alternatively, further modifications may be made to 1E, such as modifications at G, before the removal of any protecting groups to give compounds of General Formula I. Specific steps in the synthetic process are described in more detail below.

In Scheme 1, Step (i), compounds of structure 1A may be coupled under a range of conditions to compounds of structure 1B′, where B′ is an appropriate ring to afford compounds of the type 1B. The introduction of the B′ ring may require a number of steps and the preparation of a number of intermediates. Protecting groups may also be required. If R¹ is a suitable group (such as a halide or triflate), 1B′ can be converted to 1B by formation of a carbon-carbon bond. The carbon-carbon bond can be formed by reacting compounds of structure 1B′ where R³ is a borane, boronate or boronic acid group (such as a 2-formylfuran-3-boronate) in the presence of a palladium catalyst (such as palladium chloride dppf or tris-(dibenzylideneacetone)-dipalladium), in the presence of a base (such as cesium carbonate) and a suitable reagent (such as a phosphine, for example, tri-tert-butyl-phosphonium tetrafluoroborate or triphenylphosphine) in an appropriate solvent (such as dioxane, water or tetrahydrofuran, or mixtures thereof) and under appropriate conditions (such as heating, for example heating at 80-120° C. for 1-2 hours or microwave irradiation at 120-160° C. for 10 minutes to 1 hour) to afford 1B. A wide range of appropriate reagents and conditions are known to those skilled in the art to couple organoboranes, boronates and boronic acids to compounds such as 1A. [For example, see Miyaura, Suzuki, Chem. Rev. 1995, 95, 2457; Suzuki, Modern Arene Chemistry 2002, 53-106].

Alternatively the carbon-carbon bond in Scheme 1, Step (i) can be formed by coupling compounds of structure 1B′ in which B′ is an appropriate ring and where R³ is a trialkylstannane (such as a tri-n-butylstannane) with compounds of structure 1A where R¹ is a suitable group (such as a halide of triflate) in the presence of a palladium catalyst (such as palladium chloride dppf), in an appropriate solvent (such as dimethoxyethane or tetrahydrofuran) and under appropriate conditions (such as heating, at 80-120° C. for 1-2 hours or by microwave irradiation at 120-160° C. for 10 minutes to 1 hour) to afford 1B. A wide range of appropriate reagents and conditions are known to those skilled in the art to couple stannanes to aryl halides such as 1A. [For example, see Smith, March, March's Advanced Organic Chemistry, 5^(th) Edition, Wiley: New York, 2001, pp. 931-932; De Souza, Current Organic Synthesis 2006, 3(3), 313-326.].

Alternatively compounds of structure 1A, where R¹ is a suitable group (such as a halide or triflate), can be treated with, for example, a diboronate (such as bis-pinacolatodiboron) in the presence of a palladium catalyst (such as palladium chloride dppf) and a base (such as potassium acetate or diisopropylamine) in an appropriate solvent (such as a mixture of dioxane and water) and under appropriate conditions (such as heating, for example at 80-120° C. for 1-2 hours or by microwave irradiation at 120-160° C. for 10 minutes to 1 hour) to give a compound of structure 1A, where R¹ is a boronate. A wide range of appropriate reagents and conditions are known to those skilled in the art to convert an aryl halide (or aryl triflate) to an arylboronate (or an arylborane) [for example, see Marshall Chemtracts 2000, 13(4), 219-222]. The arylboronate (or arylborane) thus formed, can then be treated with compounds of structure 1B′ (where R³ is a halogen or triflate) in the presence of suitable reagents such as a phosphine (for example tri-tert-butyl-phosphonium tetrafluoroborate), a base (such as cesium carbonate) and a catalyst (such as tris-(dibenzylideneacetone)-dipalladium) in an appropriate solvent (such as a mixture of water and dioxane) under appropriate conditions (such as heating at 80-120° C. for 1-2 hours or by microwave irradiation at 120-160° C. for 10 minutes to 1 hour) to afford compounds of structure 1B.

In Scheme 1, Step (iv), the groups R² and R⁴ of compound 1B can be coupled together to give the group X′, which forms the D′-ring. R² or R⁴ may have been masked by protecting groups during Step (i), and may require deprotection before the group X′ can be formed. Alternatively, R² or R⁴ may require chemical modification before the group X′ can be formed. For example if R² or R⁴ is a nitro group, that group may be reduced, for example using hydrogen in the presence of a suitable catalyst (such as palladium on a solid support, such as carbon); or by treatment with an inorganic reducing agent (such as tin (II) chloride in DMF) to give an amino group. For example, if R² or R⁴ is a hydroxyalkyl group, that group may be treated with an oxidising agent (such as Jones reagent or manganese dioxide) to give an aldehyde; or with a different oxidising agent (such as potassium permanganate) to give a carboxylic acid. For example, if R² or R⁴ is an aldehyde, that group may be treated with an oxidising agent (such as potassium permanganate) to give a carboxylic acid or with a reducing agent (such as sodium borohydride) to give an alcohol. For example, if R² or R⁴ is a ketone, that group may be treated with a reducing agent (such as sodium borohydride) to give a secondary alcohol. For example, if R² or R⁴ is a carboxylic acid or ester, that group may be treated with a reducing agent (such as lithium aluminium hydride) to give an alcohol. For example, if R² or R⁴ is an alkene group, that group may be treated with a borane (such as 9-borobicyclononane) and converted to a primary or secondary alcohol.

Formation of the linker X′ may be carried out in a number of ways known to those skilled in the art. For example, if one of the two groups R² and R⁴ is a hydroxyl and the other is a substituted alkylalcohol then 1B can be treated with a dehydrating agent (such as diisopropyl azodicarboxylate) in the presence of a phosphine, (such as triphenylphosphine) to give 1E, where X′ is an ether. Alternatively, if one of the two groups R² or R⁴ is a hydroxyl and the other group is an alkyl group substituted with a leaving group (such as a halogen, tosylate or triflate) 1B can be treated with a base (such as diisopropylethylamine, potassium carbonate or sodium hydride) to form 1E, where X′ is an ether.

Alternatively, if one of the groups R² or R⁴ is a carboxylic acid and the other group is an alkyl halide or sulfonate, then 1B can be treated with a base such as diisopropylethylamine, potassium carbonate or sodium hydride to form 1E, where X′ is an ester.

Alternatively, if one of the two groups R² or R⁴ is a hydroxyl, or substituted alkylalcohol and the other group is a carboxylic acid or carboxylic ester, then 1B can be treated with an acid (such as hydrochloric acid) or dehydrating agent (such as dicyclohexylcarbodiimide or acetic anhydride) to form 1E, where X′ is an ester.

Alternatively, if one of the two groups R² or R⁴ on 1B is a hydroxyl or substituted alkylalcohol and the other group is a carboxylic acid, then the carboxylic acid can first be converted to a mixed anhydride (for example by treatment with 2,4,6-trichlorobenzoyl chloride) or to an activated ester (for example by treatment with HATU in the presence of a base such as diisopropylethylamine or pyridine), and the resulting mixed anhydride or activated ester can be further treated with a base (such as diisopropylethylamine, pyridine or potassium carbonate) to form 1E, where X′ is an ester.

Alternatively, if one of the groups R² or R⁴ on 1B is an amine or a substituted alkylamine and the other group is a carboxylic acid, the carboxylic acid can be converted to an activated ester (for example by treatment with HATU and a base such as diisopropylethylamine or pyridine or TBTU in the presence of N-methylmorpholine), and the resulting activated ester can be further treated with a base to form 1E where X′ is an amide.

Alternatively, if one of the two groups R² or R⁴ on 1B is an amine, or a substituted alkylamine and the other group is a carboxylic acid, then 1B can then be treated with a dehydrating agent (such as such as diisopropylcarbodiimide) to form 1E, where X′ is an amide.

Alternatively, if one of the two groups R² or R⁴ is an amine, or substituted alkylamine and the other group is an alkyl group substituted with a leaving group (such as a halogen, tosylate or triflate) then 1B can be treated with a base (such as diisopropylethylamine, pyridine or potassium carbonate) to form 1E, where X′ is a substituted amine.

Alternatively, if one of the two groups R² or R⁴ is an aldehyde, and the other group is a phosphorane (such as an alkyl triphenylphosphorane) or an alkyl phosphonate (such as an alkyl phosphonic acid diethyl ester) then 1B can be treated with a base (such as diisopropylethylamine, potassium carbonate or sodium hexamethyldisilazide) to form 1E, where X′ is an alkene which may, or may not be further substituted.

Alternatively, if one of the two groups R² or R⁴ is an amine and the other group is an aldehyde then 1B can be treated with an acid (such as p-toluenesulfoniic acid) or a Lewis acid (such as tin tetrachloride) to give 1E, where X′ is —CR═N— or —N═CR—.

In Scheme 1, Step (ii), compounds of the structure 1A can be reacted with 1C′ to form the linker X′ and give compounds of the structure 1C. The formation of the linker X′ in compounds with the structure 1C may require a number of steps and the preparation of a number of intermediates, and the use of protecting groups may also be required.

For example, if one of the two groups R² or R⁶ is a hydroxyl group and the other group is a substituted alkylalcohol then 1A and 1C′ can be treated with a dehydrating agent (such as diisopropyl azodicarboxylate) in the presence of a phosphine, (such as triphenylphosphine) to give 1C, where X′ is an ether. Alternatively, if one of the two groups R² or R⁴ is a hydroxyl and the other group is an alkyl group substituted with a leaving group (such as a halogen, or a mesylate) 1A and 1C′ can be treated with a base (such as diisopropylethylamine, potassium carbonate or sodium hydride) to form 1C, where X′ is an ether.

Alternatively, in Scheme 1, Step (ii), if one of the two groups R² or R⁶ is a hydroxyl, or alkylalcohol and the other group is a carboxylic acid, then the carboxylic acid can be converted to an acyl halide (for example by treatment with thionyl chloride or oxalyl chloride), or to a mixed anhydride (for example by treatment with 2,4,6-trichlorobenzoyl chloride in the presence of a base such as diisopropylethylamine) or to an activated ester (for example by treatment with HATU in the presence of a base such as diisopropylethylamine or pyridine, or treatment with diisopropylcarbodiimide in the presence of HOBT), then 1A and 1C′ can be combined to form 1C, where X′ is an ester.

Alternatively, if one of the two groups R² or R⁶ is an amine, or alkylamine and the other group is a carboxylic acid, then the carboxylic acid can be converted to an acyl halide (for example by treatment with thionyl chloride or oxalyl chloride), or to a mixed anhydride (for example by treatment with 2,4,6-trichlorobenzoyl chloride in the presence of a base such as diisopropylethylamine), or to an activated ester (for example by treatment with HATU in the presence of disopropylethylamine or pyridine, or treatment with diisopropylcarbodiimide in the presence of HOBT), then 1A and 1C′ can be combined to form 1C, where X′ is an amide.

Alternatively, if one of the two groups R² or R⁶ is an amine, or substituted alkylamine and the other group is an alkyl group substituted with a leaving group (such as a halogen, or a triflate) then 1A and 1C′ can be treated with a base (such as diisopropylethylamine, pyridine or potassium carbonate) to form 1C, where X′ is a substituted amine.

Alternatively, if one of the two groups R² or R⁶ is an aldehyde, and the other group is a phosphorane (such as an alkyltriphenylphosphorane) or an alkylphosphonate (such as an alkylphosphonic acid diethyl ester) then 1A and 1C′ can be treated with a base (such as diisopropylethylamine or potassium carbonate or sodium hexamethyldisilazide) to form 1C, where X′ is an alkene which may, or may not be further substituted.

In Scheme 1, Step (v), compounds of structure 1E may be prepared from compounds of structure 1C by reaction of the groups R¹ and R⁵ under a range of conditions to form a carbon-carbon bond. If one of the groups R¹ or R⁵ is a suitable group (such as a halide or triflate), and the other group is a borane, boronate or boronic acid then, in the presence of a palladium catalyst (such as palladium chloride dppf), and in the presence of a base (such as cesium carbonate), in an appropriate solvent (such as dioxane, water or tetrahydrofuran or mixtures thereof) and under appropriate conditions (such as heating, for example heating at 80-120° C. for 1-2 hours or microwave irradiation at 120-160° C. for 10 minutes to 1 hour), 1C can be converted into 1E. A wide range of appropriate reagents and conditions are known to those skilled in the art to couple organoboranes, boronates and boronic acids to give compounds of the type 1E.

Alternatively, if one of the groups R¹ or R⁵ is a suitable group (such as a halide or triflate), and the other group is a trialkylstannane, the carbon-carbon bond can be formed in the presence of a palladium catalyst (such as palladium chloride dppf), in an appropriate solvent (such as dimethoxyethane or tetrahydrofuran) and under appropriate conditions (such as heating, at 80-120° C. for 1-2 hours or by microwave irradiation at 120-160° C. for 10 minutes to 1 hour) to afford 1E. A wide range of appropriate reagents and conditions are known to those skilled in the art to couple aryl or heteroaryl stannanes to aryl or heteroaryl halides.

In Scheme 1, Step (iii), compounds of structure 1A may be reacted under a range of conditions with intermediates of the type 1D′ to give compounds of structure 1D where D′ is a six- or seven-membered fused heterocyclic ring and R⁹ and R¹⁰ are suitable functional groups that may be used to form the B′-ring. The groups R¹ and R⁷ may be reacted together to form a carbon-carbon bond, and the groups R² and R⁸ may be reacted together to form the group X′. Methods to form bicyclic compounds of structure 1D from substituted phenyl rings of structure 1A are well known to those skilled in the art (see Comprehensive Heterocyclic Chemistry Ed.: Katritzky, Ramsden, Scriven, and Taylor, Elsevier, 2008).

For example, a compound of structure 1A, where R² is a hydroxyl group and R¹ is hydrogen, can be treated with a suitably protected and substituted 3-halo-propanoic acid or ester in an appropriate solvent (such as tetrahydrofuran or dimethylformamide) and in the presence of a base (such as sodium carbonate or diisopropylethylamine) at a temperature between room temperature and the reflux temperature of the solvent to give a compound of the type 1A, where R² is a substituted oxypropanoic acid or ester. This intermediate may be treated with a suitable reagent (such as a strong acid, for example triflic acid) to give 1D where R⁹ is oxo, R¹⁰ is hydrogen and X′ is —OCH₂—.

Alternatively, a compound of structure 1A, where R² is a hydroxyl and R¹ is hydrogen, can be treated with a propargyl halide or tosylate in the presence of a base (such as potassium carbonate or cesium carbonate) in a solvent (such as acetone) at a temperature between room temperature and the reflux temperature of the solvent to give a compound of type 1A in which R² is a propargyloxyl group. This intermediate may be heated to ˜200° C. or treated with an appropriate catalyst (such as a gold catalyst, for example triphenylphosphine gold triflamide) in an appropriate solvent (such as toluene) at a temperature between 80° C. and the reflux temperature of the solvent to give a compound of structure 1D wherein X′ is —OCH₂—, R⁹ and R¹⁰ are H and the bond between is a double bond (i.e. a chromene).

Further modification of the intermediates of structure 1D having a double bond between the carbons that R⁹ and R¹⁰ are attached to (such as a chromene) may be achieved, for example, by treatment with a hydroborating agent (such as borane-THF complex) followed by oxidation with, for example, hydrogen peroxide to give a mixture of compounds of structure 1D wherein X′ is OCH₂, R⁹ is H and R¹⁰ is a hydroxyl group and wherein X′ is —OCH₂—, R⁹ is a hydroxyl and R¹⁰ is H which may be separated by chromatography.

Further modification of an intermediate of structure 1D in which one of R⁹ and R¹⁰ is H and the other is a hydroxyl may be carried out. For example, the intermediate may be oxidized by treatment with an oxidizing agent (such as Dess Martin periodinane) to give a compound of structure 1D in which one of R⁹ and R¹⁰ is H the other is oxo.

Alternatively, a compound of structure 1A in which R¹ is an appropriate group (such as a halogen, for example bromine or iodine, or a triflate) and R² is a protected amine (such as an acetamide or a trifluoroacetamide) may be coupled with a terminal alkyne in the presence of a palladium catalyst (such as tetrakis(triphenylphosphine) palladium (0)) optionally in the presence of an additional copper catalyst (such as copper (I) iodide) in the presence of a base or salt (such as triethylamine or potassium acetate), in a solvent (such as tetrahydrofuran or dimethylformamide) at a temperature between room temperature and the reflux temperature of the solvent or by irradiation in the microwave at a temperature between 100° C. and 160° C. to give a compound of structure 1A in which R¹ is a substituted alkyne and R² is a protected amine (such as an acetamide or a trifluoroacetamide). Alternatively, a compound of structure 1A in which R¹ is an appropriate group (such as a halogen, for example bromine or iodine, or a triflate) and R² is a protected amine (such as an acetamide or a trifluoroacetamide) may be coupled with an acetylenic stannane in the presence of a palladium catalyst (such as palladium chloride dppf) in an appropriate solvent (such as dioxane, dimethoxyethane or tetrahydrofuran) at a temperature between room temperature and the reflux temperature of the solvent or alternatively by irradiation in the microwave at a temperature between 100° C. and 160° C. to give a compound of structure 1A in which R¹ is an alkyne and R² is a protected amine (such as an acetamide or a trifluoroacetamide).

In Scheme 1, Step (iii), a compound of structure 1A in which R¹ is an appropriately substituted alkyne and R² is a protected amine (such as an acetamide of a trifluoroacetamide) may be treated with a base (such as potassium carbonate or sodium methoxide) in an appropriate solvent (such as acetone, DMF or methanol) at a temperature between room temperature and the reflux temperature of the solvent to give a compound of structure 1D in which X′ is NH. Alternatively, a compound of structure 1A in which R¹ is an appropriately substituted alkyne and R² is a protected amine (such as an acetamide of a trifluoroacetamide) may be treated with a palladium catalyst (such as bis-(triphenylphosphine)palladium chloride) in the presence of a base (such as triethylamine) and an appropriate catalyst (such as copper(I) iodide) in a solvent (such as dimethylformamide) at a temperature between room temperature and the reflux temperature of the solvent to give a compound of structure 1D in which X′ is NH.

The general synthetic strategy to elaborate 1D is shown in Scheme 2.

In Scheme 2, compounds of structure 1D may be converted to a variety of compounds of structure 1E using reactions known to those skilled in the art. In some cases modifications to the groups R⁹ and R¹⁰ in 1D may be required in order to be able to generate the require ring systems. One skilled in the art will recognize that it may be necessary for various functional groups to be protected prior to reaction. Specific steps in the synthetic procedures are described in more detail below.

In Scheme 2, Step (i), 1D in which R⁹ and R¹⁰ are both H and the bond between the carbon atoms is a double bond, may be treated with diethyl zinc and di-iodomethane optionally in the presence of additional reagents (such as trifluoroacetic acid or zinc iodide) in a solvent (such as 1,2-dichloroethane) at a temperature between −78° C. and room temperature to give compounds of structure 2A in which the B′ ring is a cyclopropyl ring. Alternatively, compounds of structure 1D in which R⁹ and R¹⁰ are both H and the bond between the carbon atoms is a double bond, may be treated with trimethyl sulfoxonium iodide or trimethyl sulphonium iodide in the presence of a base (such as sodium hydride) in a solvent (such as dimethyl sulfoxide) at a temperature between room temperature and 100° C. Alternatively, compounds of structure 1D in which R⁹ and R¹⁰ are both H and the bond between the carbon atoms is a double bond, may be treated with diazomethane in the presence of a catalyst (such as palladium acetate) in a solvent such as diethyl ether at a temperature between 0° C. and room temperature.

Alternatively, compounds of structure 2A may be prepared in a two step procedure. For example, in Scheme 2, Step (ii), 1D in which R⁹ and R¹⁰ are both H and the bond between the carbon atoms is a double bond, may be treated with trimethylsilyl diazomethane in the presence of a catalyst (such as palladium acetate) in a solvent (such as diethyl ether) at a temperature between 0° C. and room temperature to give the intermediate 2A′ in which J is H and J′ is a trimethyl silyl group. In Scheme 2, Step (iii), intermediates 2A′ in which J is H and J′ is a trimethyl silyl group may be converted to compounds of structure 2A by treatment with a source of fluoride, (for example tetrabutyl ammonium fluoride) in a solvent (such as tetrahydrofuran) at a temperature between 0° C. and room temperature.

Alternatively in Scheme 2, Step (ii), 1D in which R⁹ and R¹⁰ are both H and the bond between the carbon atoms is a double bond, may be treated with a haloform (such as chloroform or bromoform) in the presence of a base such as sodium hydroxide or potassium t-butoxide in the presence of a catalyst (such as triethylbenzylammonium chloride or tetrabutyl ammonium bromide) in a mixture of water and a halogenated solvent (such as dicloromethane or dichloroethane) or alternatively in excess of the haloform at a temperature between room temperature and 80° C. to give the intermediate 2A′ in which J and J′ are both chlorine or bromine. In Scheme 2, Step (iii), the intermediates 2A′ in which J and J′ are both chlorine or bromine may be converted to compounds of structure 2A by treatment with a base (such as sodium methoxide or sodium t-butoxide) in a solvent (such as tetrahydrofuran) at a temperature between room temperature and the reflux temperature of the solvent. Alternatively, the intermediates 2A′ in which J and J′ are both chlorine or bromine may be converted to compounds of structure 2A by reduction; for example, by treatment with lithium aluminium hydride in a solvent (such as tetrahydrofuran) at a temperature between 0° C. and the reflux temperature of the solvent or alternatively, for example by hydrogenation using a catalyst (such as palladium on carbon) in a solvent (such as methanol or ethanol), optionally in the presence of a base (such as triethylamine) Alternatively, the intermediates 2A′ in which J and J′ are both chlorine or bromine may be converted to compounds of structure 2A under radical conditions; for example, by treatment with a tin hydride (such as tributyl tin hydride) optionally in the presence of a radical initiator (such as azo-bis-isobutyronitrile) in a solvent (such as toluene) at a temperature between room temperature and the reflux temperature of the solvent.

In Scheme 2, Step (iv), 1D in which X′ includes a carbonyl (for example where X′ is —O—C(O)—) and R⁹ and R¹⁰ are both H and the bond between the carbon atoms is a double bond, may be converted to the corresponding compounds 2B by treatment with ethylene in a solvent (such as dichloromethane) under photochemical conditions.

Alternatively compounds of structure 2B may be prepared in a multi-step procedure. For example, in Scheme 2, Step (v), 1D in which both R⁹ and R¹⁰ are both H and the bond between the two carbon atoms is a double bond may be treated with an acrylate (such as ethyl acrylate) in a solvent (such as acetonitrile) under photochemical conditions to give an intermediate 2B′ in which J″ is an ester group (such as an ethyl ester). The ester may be hydrolysed by, for example, treatment with sodium hydroxide or lithium hydroxide in a solvent such as aqueous ethanol or aqueous dioxane at a temperature between room temperature and the reflux temperature of the solvent to give an intermediate of structure 2B′ in which J″ is a carboxylic acid. In Scheme 2, Step (vi), the acid may be removed for example by heating in, for example, quinoline optionally in the presence of a catalyst (such as copper) to around 200° C.

In Scheme 2, Step (vii), 1D in which R¹⁰ is a hydroxyl and R⁹ is a group CH₂OH may be treated with a sulfonyl chloride (such as 4-toluenesulfonyl chloride or methanesulfonyl chloride) in the presence of a base (such as triethylamine), optionally in the presence of 4-dimethylaminopyridine, in a solvent (such as dichloromethane or toluene) at a temperature between room temperature and the reflux temperature of the solvent. The product may be treated with a base (such as triethylamine, diisopropylethylamine or sodium hydride) in an appropriate solvent (such as dichloromethane, tetrahydrofuran or DMF) to give a compound of structure 2C.

In Scheme 2, Step (viii), 1D in which R⁹ is CH₂CH₂OH and R¹⁰ is CH₂OH may be converted to compounds 2D. One of the hydroxyl groups may need to be protected and the other is treated with a sulfonyl chloride (such as 4-toluenesulfonyl chloride or methanesulfonyl chloride) in the presence of a base (such as triethylamine) optionally in the presence of 4-dimethylaminopyridine, in a solvent (such as dichloromethane or toluene) at a temperature between room temperature and the reflux temperature of the solvent. After deprotection of the remaining hydroxyl group, the intermediate may be treated with a base (such as triethylamine, diisopropylethylamine or sodium hydride) in a solvent (such as dichloromethane, tetrahydrofuran or dimethylformamide at a temperature between room temperature and the reflux temperature of the solvent to give a compound of structure 2D.

Alternatively, compounds of structure 2D may be prepared in a 2 step procedure. For example, in Scheme 2, Step (ix), 1D in which R⁹ is CH₂CO₂H and R¹⁰ is CH₂OH may be converted to compounds of structure 2D′. The carboxylic acid may be converted to an acid chloride (by treatment with, for example, thionyl chloride or oxalyl chloride, optionally in the presence of a catalytic amount of DMF in a solvent such as dichloromethane or toluene) or to a mixed anhydride (for example by treatment with 2,4,6-trichlorobenzoyl chloride in the presence of a base such as diisopropylethylamine) or to an activated ester (for example by treatment with HATU in the presence of a base such as diisopropylethylamine or pyridine, or treatment with diisopropylcarbodiimide in the presence of HOBT). The acid chloride, mixed anhydride or activated ester may then be treated with a base (such as triethylamine or pyridine), in a solvent (such dichloromethane or toluene) to give the compound of structure 2D′. In Scheme 2, Step (x), compounds of structure 2D′ may be converted to compounds of structure 2D by reduction, for example, by treatment with lithium aluminium hydride, sodium diisobutylaluminium hydride or borane-dimethyl sulfide complex, in an appropriate solvent (such as tetrahydrofuran) at a temperature between −78° C. and room temperature.

In Scheme 2, Step (xi), 1D in which R⁹ is CH₂CH₂OH and R¹⁰ is a hydroxyl may be treated with a sulfonyl chloride (such as 4-toluenesulfonyl chloride or methanesulfonyl chloride) in the presence of a base (such as triethylamine), optionally in the presence of 4-dimethylaminopyridine, in a solvent (such as dichloromethane or toluene) at a temperature between room temperature and the reflux temperature of the solvent, followed by treatment with a base (such as triethylamine, diisopropylethylamine or sodium hydride) in an appropriate solvent (such as dichloromethane, tetrahydrofuran or DMF) at a temperature between room temperature and the reflux temperature of the solvent to give a compound of structure 2E.

Alternatively, compounds of structure 2E may be prepared in a 2 step procedure. In Scheme 2, Step (xii), 1D in which R⁹ is H and R¹⁰ is oxo may be converted to compounds of structure 2E′ by treatment with chloroacetaldehyde or bromoacetaldehyde in the presence of an aqueous base (such as sodium bicarbonate or sodium hydroxide in water) at a temperature between 0° C. and room temperature, followed by treatment with an acid (such as concentrated sulfuric acid) in a mixture of water and an organic solvent (such as ethyl acetate).

In Scheme 2, Step (xiii), compounds of structure 2E may be prepared from compounds of structure 2E′ by hydrogenation in the presence of a metal catalyst (such as palladium or palladium hydroxide on a solid support such as carbon) in a solvent (such as an ether, for example tetrahydrofuran or dioxane, or an alcohol, such as methanol or ethanol), optionally in the presence of an acid (such as acetic acid). Depending upon the nature of the linker X′, the bond between the two rings may be reduced or not to give either a tetrahydrofuran or a dihydrofuran. For example, if X′ is —N═C— then the B′ ring in 2E will be a dihydrofuran whereas if X′ is —OCH₂— then the B′ ring will be a tetrahydrofuran.

In Scheme 1, Step (vii), compounds of general structure 1E may be converted to compounds of General Formula I by the conversion of the group G′ to a carboxylic acid. If the group G′ is a carboxylic ester (such as a methyl, tert-butyl or benzyl ester) then a variety of reagents and conditions can be used to convert 1E into a compound of the General Formula I. For example, if G′ is a methyl, ethyl or benzyl ester, it may be converted to a carboxylic acid by treatment with an inorganic base (such as lithium hydroxide or sodium hydroxide) in a solvent (such as methanol, dioxane or water, or mixtures thereof) at a temperature between room temperature and the reflux temperature of the solvent, or alternatively by microwave irradiation at 120-180° C. for 10 minutes to 1 hour. Alternatively if G′ is a benzyl ester it may be converted to a carboxylic acid by hydrogenation in the presence of a catalyst (such as palladium on a solid support such as carbon) in a solvent (such as dioxane or ethyl acetate). Alternatively if G′ is a tert-butyl ester, it may be converted to a carboxylic acid by treatment with an acid (such as trifluoromethanesulfonic acid or hydrogen chloride) in a solvent (such as dichloromethane or dioxane).

Alternatively, if the group G′ is a nitrile, it may be converted into a carboxylic acid by treatment with aqueous acid (such as a mineral acid, for example hydrochloric acid) under appropriate conditions (such as heating, for example to reflux); or by treatment with aqueous base (such as an aqueous hydroxide, for example aqueous sodium hydroxide) under appropriate conditions (such as heating, for example to reflux).

Alternatively, if the group G′ is an aldehyde (CHO) or a hydroxymethyl (CH₂OH) moiety then it may be converted into a carboxylic acid by treatment with a suitable oxidising reagent (such as potassium permanganate or chromic acid).

The general synthetic strategy to modify the group G is depicted in Scheme 3. The G group may be introduced and/or modified either before, during or after the assembly of the tricyclic ring system. Specific steps used to assemble sulfonamide are described in more detail below.

In Scheme 3, the asterisks denote either the presence of the groups R¹ and R² (as shown in Scheme 1) or the presence of the D′ and B′ rings, or intermediates towards the preparation of the rings (as shown in Schemes 1 and 2).

In Scheme 3, Step (i), compounds of structure 3A in which G is a nitro group may be converted to compounds 3B by reduction, for example by catalytic hydrogenation in the presence of a metal catalyst (such as palladium on a solid support such as carbon) in a solvent (such as an ether, for example tetrahydrofuran, or an alcohol, for example methanol or ethanol). Alternatively, compounds of structure 3A in which G is a nitro group may be converted to compounds of structure 3B by chemical reduction. For example, the reduction may be achieved using a metal or metal salt (such as iron, zinc or tin (II) chloride) in the presence of an acid (such as hydrochloric acid or acetic acid).

In Scheme 3, Step (i), compounds of structure 3A in which G is a protected amino group may be converted to compounds of structure 3B by removal of the protecting groups. Protecting groups for amino groups are well known to those skilled in the art and methods for their removal are equally well known [for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)]. For example, compounds of structure 3A in which F is an amino group protected with one or two Boc groups may be converted to compounds of structure 3B by treatment with an acid (such as trifluoroacetic acid, formic acid or hydrogen chloride) in a solvent (such as dichloromethane or dioxane).

Alternatively, in Scheme 3, Step (i), compounds of structure 3A in which G is a pivaloyl protected aniline may be converted to compounds of structure 3B by treatment with an acid (such as concentrated sulfuric acid) in a solvent (such as methanol) at a temperature between room temperature and the reflux temperature of the solvent.

In Scheme 3, Step (ii), compounds of structure 3B may be converted to compounds of structure 3C by treatment with an appropriate sulfonyl chloride (such as a substituted or unsubstituted benzene sulfonyl chloride) or an activated sulfonate ester (such as a pentafluorophenyl sulfonate ester) in the presence of a suitable base (such as pyridine, diisopropylethylamine or cesium carbonate) in a suitable solvent (such as dichloromethane or dimethylformamide) at a temperature between room temperature and the reflux temperature of the solvent.

Intermediates towards the preparation of compounds of Formula 1 or, for example, General Formula 1 may require reduction of an aromatic ring system to give the saturated ring system required in the compounds of Formula 1. This hydrogenation may be carried out by hydrogenation of the intermediates in the presence of a metal catalyst (for example palladium or palladium hydroxide on a solid support, such as carbon) in a solvent (such as ethanol, ethyl acetate or dioxane) optionally in the presence of an acid (such as acetic acid). The reduction of the aromatic rings may be carried out before the formation of the tricyclic ring system or after it or at any stage during the synthesis as will be recognized by those skilled in the art.

Compounds of any of Formula I, Formula II or, for example, General Formula I as depicted above, or any of the intermediates described in the schemes above, can be further derivatised by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify compounds of General Formula I or any preceding intermediates by modifying, introducing or removing appropriate functional groups. Particular substitution approaches include alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulfonylation, nitration, formylation, hydrolysis and coupling procedures. These procedures can be used to introduce a functional group onto the parent molecule (such as the nitration or sulfonylation of aromatic rings) or to couple two molecules together (for example to couple an amine to a carboxylic acid to afford an amide; or to form a carbon-carbon bond between two heterocycles). For example, alcohol or phenol groups can be converted to ether groups by coupling a phenol with an alcohol in a solvent (such as tetrahydrofuran) in the presence of a phosphine (such as triphenylphosphine) and a dehydrating agent (such as diethyl, diisopropyl or dimethyl azodicarboxylate). Alternatively, ether groups can be prepared by deprotonation of an alcohol, using a suitable base (such as sodium hydride) followed by the addition of an alkylating agent (such as an alkyl halide or an alkyl sulfonate).

In another example, a primary or secondary amine can be alkylated using a reductive alkylation procedure. For example, the amine can be treated with an aldehyde and a borohydride (such as sodium triacetoxyborohydride, or sodium cyanoborohydride in a solvent (such as a halogenated hydrocarbon, for example dichloromethane, or an alcohol, for example ethanol) and, where necessary, in the presence of an acid (such as acetic acid).

In another example, hydroxy groups (including phenolic OH groups) can be converted into leaving groups, such as halogen atoms or sulfonyloxy groups (such as alkylsulfonyloxy, for example trifluoromethanesulfonyloxy, or aryl suphonyloxy, for example p-toluenesulfonyloxy) using conditions known to those skilled in the art. For example, an aliphatic alcohol can be reacted with thionyl chloride in a halogenated hydrocarbon (such as dichloromethane) to afford the corresponding alkyl chloride. A base (such as triethylamine) can also be used in the reaction.

In another example, ester groups can be converted to the corresponding carboxylic acid by acid- or base-catalysed hydrolysis depending on the nature of the ester group. Acid catalysed hydrolysis can be achieved by treatment with an organic or inorganic acid (such as trifluoroacetic acid in an aqueous solvent, or a mineral acid such as hydrochloric acid in a solvent such as dioxane). Base catalysed hydrolysis can be achieved by treatment with an alkali metal hydroxide (such as lithium hydroxide in an aqueous alcohol, for example methanol).

In another example, aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange by treatment with a base (such as a lithium base, for example n-butyl or t-butyl lithium) optionally at a low temperature (such as −78° C.) in a solvent (such as tetrahydrofuran) and the mixture may then be quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group can be introduced by using dimethylformamide as the electrophile. Aromatic halogen substituents can also be subjected to palladium catalysed reactions to introduce groups such as carboxylic acids, esters, cyano or amino substituents.

In another example, an aryl, or heteroaryl ring substituted with an appropriate leaving group (such as a halogen or sulfonyl ester, for example a triflate) can undergo a palladium catalysed coupling reaction with a wide variety of substrates to form a carbon-carbon bond. For example, a Heck reaction can be used to couple such a ring system to an alkene (which may, or may not, be further substituted) by treatment with an organopalladium complex (such as tetrakis(triphenylphosphine)palladium(0), palladium (II) acetate or palladium (II) chloride) in the presence of a ligand (such as a phosphine, for example triphenylphosphine) in the presence of a base (such as potassium carbonate or a tertiary amine, for example, triethylamine), in an appropriate solvent (such as tetrahydrofuran or DMF), under appropriate conditions (such as heating to, for example, 50-120° C.). In another example, a Sonogashira reaction can be used to couple such a ring system to an alkyne (which may, or may not be further substituted) by treatment with a palladium complex (such as tetrakis(triphenylphosphine)palladium(0)) and a halide salt of copper (I) (such as copper (I) iodide), in the presence of a base (such as a potassium carbonate or a tertiary amine, for example, triethylamine), in an appropriate solvent (such as tetrahydrofuran or dimethylformamide), under appropriate conditions (such as heating to, for example, 50-120° C.). In another example, a Stille reaction can be used to couple such a ring system to an alkene, by treatment with an organotin compound (such as an alkynyltin or alkenyltin reagent, for example an alkenyltributylstannane) in the presence of a palladium complex (such as tetrakis(triphenylphosphine)palladium(0)), with, or without the presence of a salt (such as a copper (I) halide), in an appropriate solvent (such as dioxane or dimethylformamide), under appropriate conditions (such as heating to, for example, 50-120° C.).

Particular oxidation approaches include dehydrogenations and aromatisation, decarboxylation and the addition of oxygen to certain functional groups. For example, aldehyde groups can be prepared by oxidation of the corresponding alcohol using conditions well known to those skilled in the art. For example, an alcohol can be treated with an oxidising agent (such as Dess-Martin periodinane) in a solvent (such as a halogenated hydrocarbon, for example dichloromethane). Alternative oxidising conditions can be used, such as treatment with oxalyl chloride and an activating amount of dimethylsulfoxide and subsequent quenching by the addition of an amine (such as triethylamine). Such a reaction can be carried out in an appropriate solvent (such as a halogenated hydrocarbon, for example dichloromethane) and under appropriate conditions (such as cooling below room temperature, for example to −78° C. followed by warming to room temperature). In another example, sulfur atoms can be oxidised to the corresponding sulfoxide or sulfone using an oxidising agent (such as a peroxy acid, for example 3-chloroperoxybenzoic acid) in an inert solvent (such as a halogenated hydrocarbon, for example dichloromethane) at around ambient temperature.

Particular reduction approaches include the removal of oxygen atoms from particular functional groups or saturation (or partial saturation) of unsaturated compounds including aromatic or heteroaromatic rings. For example, primary alcohols can be generated from the corresponding ester or aldehyde by reduction, using a metal hydride (such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol). Alternatively, CH₂OH groups can be generated from the corresponding carboxylic acid by reduction, using a metal hydride (such as lithium aluminium hydride in a solvent such as tetrahydrofuran). In another example, a nitro group may be reduced to an amine by catalytic hydrogenation in the presence of a metal catalyst (such as palladium on a solid support such as carbon) in a solvent (such as an ether, for example tetrahydrofuran, or an alcohol, such as methanol), or by chemical reduction using a metal (such as zinc, tin or iron) in the presence of an acid (such as acetic acid or hydrochloric acid). In a further example an amine can be obtained by reduction of a nitrile, for example by catalytic hydrogenation in the presence of a metal catalyst (such as palladium on a solid support such as carbon), or Raney nickel in a solvent (such as tetrahydrofuran) and under suitable conditions (such as cooling to below room temperature, for example to −78° C., or heating, for example to reflux).

Salts of compounds of General Formula I can be prepared by the reaction of a compound of General Formula I with an appropriate acid or base in a suitable solvent, or mixture of solvents (such as an ether, for example, diethyl ether, or an alcohol, for example ethanol, or an aqueous solvent) using conventional procedures. Salts of compound of General Formula I can be exchanged for other salts by treatment using conventional ion-exchange chromatography procedures.

Where it is desired to obtain a particular enantiomer of a compound of General Formula I, this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers. For example, diastereomeric derivatives (such as salts) can be produced by reaction of a mixture of enantiomers of a compound of General Formula I (such a racemate) and an appropriate chiral compound (such as a chiral base). The diastereomers can then be separated by any conventional means such as crystallisation, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Steroselective Biocatalysts, Marcel Decker; New York 2000).

In another resolution process a racemate of compounds of General Formula I can be separated using chiral High Performance Liquid Chromatography. Alternatively, a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.

II. Methods

Another aspect of the invention provides methods of modulating the activity of MetAP2. Such methods comprise exposing said receptor to a compound described herein. In some embodiments, the compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein. The ability of compounds described herein to modulate or inhibit MetAP2 can be evaluated by procedures known in the art and/or described herein. Another aspect of the invention provides methods of treating a disease associated with expression or activity of MetAP2 in a patient. For example, a contemplated method includes administering a disclosed compound in an amount sufficient to establish inhibition of intracellular MetAP2 effective to increase thioredoxin production in the patient and to induce multi organ stimulation of anti-obesity processes in the subject, for example, by administering a disclosed compound in an amount insufficient to reduce angiogenesis in the patient.

In certain embodiments, the invention provides a method of treating and or ameliorating obesity in a patient by administering an effective amount of a disclosed compound. Also provided herein are methods for inducing weight loss in a patient in need thereof. Contemplated patients include not only humans, but other animals such as companion animals (e.g., dogs, cats).

Other contemplated methods of treatment include method of treating or ameliorating an obesity-related condition or co-morbidity, by administering a compound disclosed herein to a subject. For example, contemplated herein are methods for treating type 2 diabetes in a patient in need thereof.

Exemplary co-morbidities include cardiac disorders, endocrine disorders, respiratory disorders, hepatic disorders, skeletal disorders, psychiatric disorders, metabolic disorders, and reproductive disorders.

Exemplary cardiac disorders include hypertension, dyslipidemia, ischemic heart disease, cardiomyopathy, cardiac infarction, stroke, venous thromboembolic disease and pulmonary hypertension. Exemplary endocrine disorders include type 2 diabetes and latent autoimmune diabetes in adults. Exemplary respiratory disorders include obesity-hypoventilation syndrome, asthma, and obstructive sleep apnea. An exemplary hepatic disorder is nonalcoholic fatty liver disease. Exemplary skeletal disorders include back pain and osteoarthritis of weight-bearing joints. Exemplary metabolic disorders include Prader-Willi Syndrome and polycystic ovary syndrome. Exemplary reproductive disorders include sexual dysfunction, erectile dysfunction, infertility, obstetric complications, and fetal abnormalities. Exemplary psychiatric disorders include weight-associated depression and anxiety.

In particular, in certain embodiments, the invention provides a method of treating the above medical indications comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

Obesity or reference to “overweight” refers to an excess of fat in proportion to lean body mass. Excess fat accumulation is associated with increase in size (hypertrophy) as well as number (hyperplasia) of adipose tissue cells. Obesity is variously measured in terms of absolute weight, weight:height ratio, distribution of subcutaneous fat, and societal and esthetic norms. A common measure of body fat is Body Mass Index (BMI). The BMI refers to the ratio of body weight (expressed in kilograms) to the square of height (expressed in meters). Body mass index may be accurately calculated using either of the formulas: weight (kg)/height² (m²) (SI) or 703×weight (lb)/height² (in²) (US).

In accordance with the U.S. Centers for Disease Control and Prevention (CDC), an overweight adult has a BMI of 25 kg/m² to 29.9 kg/m², and an obese adult has a BMI of 30 kg/m² or greater. A BMI of 40 kg/m² or greater is indicative of morbid obesity or extreme obesity. Obesity can also refer to patients with a waist circumference of about 102 cm for males and about 88 cm for females. For children, the definitions of overweight and obese take into account age and gender effects on body fat. Patients with differing genetic background may be considered “obese” at a level differing from the general guidelines, above.

The compounds of the present invention also are useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy. Methods for treating patients at risk of obesity, such as those patients who are overweight, but not obese, e.g. with a BMI of between about 25 and 30 kg/m², are also contemplated. In certain embodiments, a patient is a human.

BMI does not account for the fact that excess adipose can occur selectively in different parts of the body, and development of adipose tissue can be more dangerous to health in some parts of the body rather than in other parts of the body. For example, “central obesity”, typically associated with an “apple-shaped” body, results from excess adiposity especially in the abdominal region, including belly fat and visceral fat, and carries higher risk of co-morbidity than “peripheral obesity”, which is typically associated with a “pear-shaped” body resulting from excess adiposity especially on the hips. Measurement of waist/hip circumference ratio (WHR) can be used as an indicator of central obesity. A minimum WHR indicative of central obesity has been variously set, and a centrally obese adult typically has a WHR of about 0.85 or greater if female and about 0.9 or greater if male.

Methods of determining whether a subject is overweight or obese that account for the ratio of excess adipose tissue to lean body mass involve obtaining a body composition of the subject. Body composition can be obtained by measuring the thickness of subcutaneous fat in multiple places on the body, such as the abdominal area, the subscapular region, arms, buttocks and thighs. These measurements are then used to estimate total body fat with a margin of error of approximately four percentage points. Another method is bioelectrical impedance analysis (BIA), which uses the resistance of electrical flow through the body to estimate body fat. Another method is using a large tank of water to measure body buoyancy. Increased body fat will result in greater buoyancy, while greater muscle mass will result in a tendency to sink.

In another aspect, the invention provides methods for treating an overweight or obese subject involving determining a level of at least one biomarker related to being overweight or obese in the subject, and administering an effective amount of a disclosed compound to achieve a target level in the subject. Exemplary biomarkers include body weight, Body Mass Index (BMI), Waist/Hip ratio WHR, plasma adipokines, and a combination of two or more thereof.

In certain embodiments, the compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein.

The compounds of the invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. For treating clinical conditions and diseases noted above, a compound of this invention may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections or infusion techniques.

Treatment can be continued for as long or as short a period as desired. The compositions may be administered on a regimen of, for example, one to four or more times per day. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely. A treatment period can terminate when a desired result, for example a weight loss target, is achieved. A treatment regimen can include a corrective phase, during which dose sufficient to provide reduction of weight is administered, and can be followed by a maintenance phase, during which a e.g. a lower dose sufficient to prevent weight gain is administered. A suitable maintenance dose is likely to be found in the lower parts of the dose ranges provided herein, but corrective and maintenance doses can readily be established for individual subjects by those of skill in the art without undue experimentation, based on the disclosure herein. Maintenance doses can be employed to maintain body weight in subjects whose body weight has been previously controlled by other means, including diet and exercise, bariatric procedures such as bypass or banding surgeries, or treatments employing other pharmacological agents.

III. Pharmaceutical Compositions and Kits

Another aspect of the invention provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.

Exemplary pharmaceutical compositions of this invention may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Compositions and compounds of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

Pharmaceutical compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants

In another aspect, the invention provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present invention.

Advantageously, the invention also provides kits for use by a e.g. a consumer in need of weight loss. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

Also contemplated herein are methods and compositions that include a second active agent, or administering a second active agent. For example, in addition to being overweight or obese, a subject or patient can further have overweight- or obesity-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being overweight or obese. Contemplated herein are disclosed compounds in combination with at least one other agent that has previously been shown to treat these overweight- or obesity-related conditions.

For example, Type II diabetes has been associated with obesity. Certain complications of Type II diabetes, e.g., disability and premature death, can be prevented, ameliorated, or eliminated by sustained weight loss (Astrup, A. Pub Health Nutr (2001) 4:499-5 15). Agents administered to treat Type II diabetes include sulfonylureas (e.g., Chlorpropamide, Glipizide, Glyburide, Glimepiride); meglitinides (e.g., Repaglinide and Nateglinide); biguanides (e.g., Metformin); thiazolidinediones (Rosiglitazone, Troglitazone, and Pioglitazone); dipeptidylpeptidase-4 inhibitors (e.g., Sitagliptin, Vildagliptin, and Saxagliptin); glucagon-like peptide-1 mimetics (e.g., Exenatide and Liraglutide); and alpha-glucosidase inhibitors (e.g., Acarbose and Miglitol.

Cardiac disorders and conditions, for example hypertension, dyslipidemia, ischemic heart disease, cardiomyopathy, cardiac infarction, stroke, venous thromboembolic disease and pulmonary hypertension, have been linked to overweight or obesity. For example, hypertension has been linked to obesity because excess adipose tissue secretes substances that are acted on by the kidneys, resulting in hypertension. Additionally, with obesity there are generally higher amounts of insulin produced (because of the excess adipose tissue) and this excess insulin also elevates blood pressure. A major treatment option of hypertension is weight loss. Agents administered to treat hypertension include Chlorthalidone; Hydrochlorothiazide; Indapamide, Metolazone; loop diuretics (e.g., Bumetanide, Ethacrynic acid, Furosemide, Lasix, Torsemide); potassium-sparing agents (e.g., Amiloride hydrochloride, benzamil, Spironolactone, and Triamterene); peripheral agents (e.g., Reserpine); central alpha-agonists (e.g., Clonidine hydrochloride, Guanabenz acetate, Guanfacine hydrochloride, and Methyldopa); alpha-blockers (e.g., Doxazosin mesylate, Prazosin hydrochloride, and Terazosin hydrochloride); beta-blockers (e.g., Acebutolol, Atenolol, Betaxolol, Bisoprolol fumarate, Carteolol hydrochloride, Metoprolol tartrate, Metoprolol succinate, Nadolol, Penbutolol sulfate, Pindolol, Propranolol hydrochloride, and Timolol maleate); combined alpha- and beta-blockers (e.g., Carvedilol and Labetalol hydrochloride); direct vasodilators (e.g., Hydralazine hydrochloride and Minoxidil); calcium antagonists (e.g., Diltiazem hydrochloride and Verapamil hydrochloride); dihydropyridines (e.g., Amlodipine besylate, Felodipine, Isradipine, Nicardipine, Nifedipine, and Nisoldipine); ACE inhibitors (benazepril hydrochloride, Captopril, Enalapril maleate, Fosinopril sodium, Lisinopril, Moexipril, Quinapril hydrochloride, Ramipril, Trandolapril); Angiotensin II receptor blockers (e.g., Losartan potassium, Valsartan, and Irbesartan); Renin inhibitors (e.g., Aliskiren); and combinations thereof. These compounds are administered in regimens and at dosages known in the art.

Carr et al. (The Journal of Clinical Endocrinology & Metabolism (2004) Vol. 89, No. 6 2601-2607) discusses a link between being overweight or obese and dyslipidemia. Dyslipidemia is typically treated with statins. Statins, HMG-CoA reductase inhibitors, slow down production of cholesterol in a subject and/or remove cholesterol buildup from arteries. Statins include mevastatin, lovastatin, pravastatin, simvastatin, velostatin, dihydrocompactin, fluvastatin, atorvastatin, dalvastatin, carvastatin, crilvastatin, bevastatin, cefvastatin, rosuvastatin, pitavastatin, and glenvastatin. These compounds are administered in regimens and at dosages known in the art. Eckel (Circulation (1997) 96:3248-3250) discusses a link between being overweight or obese and ischemic heart disease. Agents administered to treat ischemic heart disease include statins, nitrates (e.g., Isosorbide Dinitrate and Isosorbide Mononitrate), beta-blockers, and calcium channel antagonists. These compounds are administered in regimens and at dosages known in the art.

Wong et al. (Nature Clinical Practice Cardiovascular Medicine (2007) 4:436-443) discusses a link between being overweight or obese and cardiomyopathy. Agents administered to treat cardiomyopathy include inotropic agents (e.g., Digoxin), diuretics (e.g., Furosemide), ACE inhibitors, calcium antagonists, anti-arrhythmic agents (e.g., Sotolol, Amiodarone and Disopyramide), and beta-blockers. These compounds are administered in regimens and at dosages known in the art. Yusef et al. (Lancet (2005) 366(9497):1640-1649) discusses a link between being overweight or obese and cardiac infarction. Agents administered to treat cardiac infarction include ACE inhibitors, Angiotensin II receptor blockers, direct vasodilators, beta blockers, anti-arrhythmic agents and thrombolytic agents (e.g., Alteplase, Retaplase, Tenecteplase, Anistreplase, and Urokinase). These compounds are administered in regimens and at dosages known in the art.

Suk et al. (Stroke (2003) 34:1586-1592) discusses a link between being overweight or obese and strokes. Agents administered to treat strokes include anti-platelet agents (e.g., Aspirin, Clopidogrel, Dipyridamole, and Ticlopidine), anticoagulant agents (e.g., Heparin), and thrombolytic agents. Stein et al. (The American Journal of Medicine (2005) 18(9):978-980) discusses a link between being overweight or obese and venous thromboembolic disease. Agents administered to treat venous thromboembolic disease include anti-platelet agents, anticoagulant agents, and thrombolytic agents. Sztrymf et al. (Rev Pneumol Clin (2002) 58(2):104-10) discusses a link between being overweight or obese and pulmonary hypertension. Agents administered to treat pulmonary hypertension include inotropic agents, anticoagulant agents, diuretics, potassium (e.g., K-dur), vasodilators (e.g., Nifedipine and Diltiazem), Bosentan, Epoprostenol, and Sildenafil. Respiratory disorders and conditions such as obesity-hypoventilation syndrome, asthma, and obstructive sleep apnea, have been linked to being overweight or obese. Elamin (Chest (2004) 125:1972-1974) discusses a link between being overweight or obese and asthma. Agents administered to treat asthma include bronchodilators, anti-inflammatory agents, leukotriene blockers, and anti-Ige agents. Particular asthma agents include Zafirlukast, Flunisolide, Triamcinolone, Beclomethasone, Terbutaline, Fluticasone, Formoterol, Beclomethasone, Salmeterol, Theophylline, and Xopenex.

Kessler et al. (Eur Respir J (1996) 9:787-794) discusses a link between being overweight or obese and obstructive sleep apnea. Agents administered to treat sleep apnea include Modafinil and amphetamines.

Hepatic disorders and conditions, such as nonalcoholic fatty liver disease, have been linked to being overweight or obese. Tolman et al. (Ther Clin Risk Manag (2007) 6:1153-1163) discusses a link between being overweight or obese and nonalcoholic fatty liver disease. Agents administered to treat nonalcoholic fatty liver disease include antioxidants (e.g., Vitamins E and C), insulin sensitizers (Metformin, Pioglitazone, Rosiglitazone, and Betaine), hepatoprotectants, and lipid-lowering agents.

Skeletal disorders and conditions, such as, back pain and osteoarthritis of weight-bearing joints, have been linked to being overweight or obese. van Saase (J Rheumatol (1988) 15(7):1152-1158) discusses a link between being overweight or obese and osteoarthritis of weight-bearing joints. Agents administered to treat osteoarthritis of weight-bearing joints include Acetaminophen, non-steroidal anti-inflammatory agents (e.g., Ibuprofen, Etodolac, Oxaprozin, Naproxen, Diclofenac, and Nabumetone), COX-2 inhibitors (e.g., Celecoxib), steroids, supplements (e.g. glucosamine and chondroitin sulfate), and artificial joint fluid.

Metabolic disorders and conditions, for example, Prader-Willi Syndrome and polycystic ovary syndrome, have been linked to being overweight or obese. Cassidy (Journal of Medical Genetics (1997) 34:917-923) discusses a link between being overweight or obese and Prader-Willi Syndrome. Agents administered to treat Prader-Willi Syndrome include human growth hormone (HGH), somatropin, and weight loss agents (e.g., Orlistat, Sibutramine, Methamphetamine, Ionamin, Phentermine, Bupropion, Diethylpropion, Phendimetrazine, Benzphetermine, and Topamax).

Hoeger (Obstetrics and Gynecology Clinics of North America (2001) 28(1):85-97) discusses a link between being overweight or obese and polycystic ovary syndrome. Agents administered to treat polycystic ovary syndrome include insulin-sensitizers, combinations of synthetic estrogen and progesterone, Spironolactone, Eflornithine, and Clomiphene. Reproductive disorders and conditions such as sexual dysfunction, erectile dysfunction, infertility, obstetric complications, and fetal abnormalities, have been linked to being overweight or obese. Larsen et al. (Int J Obes (Lond) (2007) 8:1189-1198) discusses a link between being overweight or obese and sexual dysfunction. Chung et al. (Eur Urol (1999) 36(1):68-70) discusses a link between being overweight or obese and erectile dysfunction. Agents administered to treat erectile dysfunction include phosphodiesterase inhibitors (e.g., Tadalafil, Sildenafil citrate, and Vardenafil), prostaglandin E analogs (e.g., Alprostadil), alkaloids (e.g., Yohimbine), and testosterone. Pasquali et al. (Hum Reprod (1997) 1:82-87) discusses a link between being overweight or obese and infertility. Agents administered to treat infertility include Clomiphene, Clomiphene citrate, Bromocriptine, Gonadotropin-releasing Hormone (GnRH), GnRH agonist, GnRH antagonist, Tamoxifen/nolvadex, gonadotropins, Human Chorionic Gonadotropin (HCG), Human Menopausal Gonadotropin (HmG), progesterone, recombinant follicle stimulating hormone (FSH), Urofollitropin, Heparin, Follitropin alfa, and Follitropin beta.

Weiss et al. (American Journal of Obstetrics and Gynecology (2004) 190(4):1091-1097) discusses a link between being overweight or obese and obstetric complications. Agents administered to treat obstetric complications include Bupivacaine hydrochloride, Dinoprostone PGE2, Meperidine HCl, Ferro-folic-500/iberet-folic-500, Meperidine, Methylergonovine maleate, Ropivacaine HCl, Nalbuphine HCl, Oxymorphone HCl, Oxytocin, Dinoprostone, Ritodrine, Scopolamine hydrobromide, Sufentanil citrate, and Oxytocic.

Psychiatric disorders and conditions, for example, weight-associated depression and anxiety, have been linked to being overweight or obese. Dixson et al. (Arch Intern Med (2003) 163:2058-2065) discusses a link between being overweight or obese and depression. Agents administered to treat depression include serotonin reuptake inhibitors (e.g., Fluoxetine, Escitalopram, Citalopram, Paroxetine, Sertraline, and Venlafaxine); tricyclic antidepressants (e.g., Amitriptyline, Amoxapine, Clomipramine, Desipramine, Dosulepin hydrochloride, Doxepin, Imipramine, Iprindole, Lofepramine, Nortriptyline, Opipramol, Protriptyline, and Trimipramine); monoamine oxidase inhibitors (e.g., Isocarboxazid, Moclobemide, Phenelzine, Tranylcypromine, Selegiline, Rasagiline, Nialamide, Iproniazid, Iproclozide, Toloxatone, Linezolid, Dienolide kavapyrone desmethoxyyangonin, and Dextroamphetamine); psychostimulants (e.g., Amphetamine, Methamphetamine, Methylphenidate, and Arecoline); antipsychotics (e.g., Butyrophenones, Phenothiazines, Thioxanthenes, Clozapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone, Amisulpride, Paliperidone, Symbyax, Tetrabenazine, and Cannabidiol); and mood stabilizers (e.g., Lithium carbonate, Valproic acid, Divalproex sodium, Sodium valproate, Lamotrigine, Carbamazepine, Gabapentin, Oxcarbazepine, and Topiramate).

Simon et al. (Archives of General Psychiatry (2006) 63(7):824-830) discusses a link between being overweight or obese and anxiety. Agents administered to treat anxiety include serotonin reuptake inhibitors, mood stabilizers, benzodiazepines (e.g., Alprazolam, Clonazepam, Diazepam, and Lorazepam), tricyclic antidepressants, monoamine oxidase inhibitors, and beta-blockers.

Another aspect of the invention provides methods for facilitating and maintaining weight loss in a subject involving administering to the subject an amount of a disclosed compound effective to result in weight loss in the subject; and administering a therapeutically effective amount of a different weight loss agent to maintain a reduced weight in the subject. Weight loss agents include serotonin and noradrenergic re-uptake inhibitors; noradrenergic re-uptake inhibitors; selective serotonin re-uptake inhibitors; and intestinal lipase inhibitors. Particular weight loss agents include orlistat, sibutramine, methamphetamine, ionamin, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetermine, bromocriptine, lorcaserin, topiramate, or agents acting to modulate food intake by blocking ghrelin action, inhibiting diacylglycerol acyltransferase 1 (DGAT1) activity, inhibiting stearoyl CoA desaturase 1 (SCD1) activity, inhibiting neuropeptide Y receptor 1 function, activating neuropeptide Y receptor 2 or 4 function, or inhibiting activity of sodium-glucose cotransporters 1 or 2. These compounds are administered in regimens and at dosages known in the art.

EXAMPLES

The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

At least some of the compounds identified as “Intermediates” herein are contemplated as compounds of the invention.

¹H NMR spectra were recorded at ambient temperature using a Varian Unity Inova (400 MHz) spectrometer with a triple resonance 5 mm probe for Example compounds, and either a Bruker Avance DRX (400 MHz) spectrometer or a Bruker Avance DPX (300 MHz) spectrometer for Intermediate compounds. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations have been used: br=broad signal, s=singlet, d=doublet, dd=double doublet, ddd=double double doublet, dt=double triplet, t=triplet, td=triple doublet, q=quartet, m=multiplet.

Mass Spectrometry (LCMS) experiments to determine retention times and associated mass ions were performed using the following methods:

Method A: Experiments were performed on a Waters ZMD LC quadruple mass spectrometer linked to a Waters 1525 LC system with a diode array detector. The spectrometer has an electrospray source operating in positive and negative ion mode. Additional detection was achieved using a Sedex 85 evaporative light scattering detector. LC was carried out using a Luna 3 micron 30×4.6 mm C18 column and a 2 mL/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.

Method B: Experiments were performed on a Waters V G Platform quadrupole spectrometer linked to a Hewlett Packard 1050 LC system with a diode array detector. The spectrometer has an electrospray source operating in positive and negative ion mode. Additional detection was achieved using a Sedex 85 evaporative light scattering detector. LC was carried out using a Luna 3 micron 30×4.6 mm C18 column and a 2 mL/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.3 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.

Method C: Experiments were performed on a Waters Micromass ZQ2000 quadruple mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector. The spectrometer has an electrospray source operating in positive and negative ion mode. LC was carried out using an Acquity BEH 1.7 micron C18 column, an Acquity BEH Shield 1.7 micron RP18 column or an Acquity HSST 1.8 micron column. Each column has dimensions of 100×2.1 mm and was maintained at 40° C. with a flow rate of 0.4 mL/minute. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.4 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 6 minutes. The final solvent system was held constant for a further 0.8 minutes.

Method D: Experiments were performed on a Waters ZMD LC quadruple mass spectrometer linked to a Hewlett Packard HD 1100 system with a diode array detector. The spectrometer has an electrospray source operating in positive and negative ion mode. LC was carried out using a Luna 3 micron 30×4.6 mm C18 column and a 2 mL/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.

Method E: Experiments were performed on a Waters Platform LC quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with diode array detector and 100 position autosampler. The spectrometer has an electrospray source operating in positive and negative ion mode. Additional detection was achieved using a Sedex 85 evaporative light scattering detector. LC was carried out using a Phenomenex Luna 3 micron 30×4.6 mm C18 column and a 2 mL/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.

Method F: Experiments were performed on a Waters ZQ quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with quaternary pump and PDA detector. The spectrometer has an electrospray source operating in positive and negative ion mode. Additional detection was achieved using a Sedex 65 evaporative light scattering detector. LC was carried out using a Phenomenex Luna 3 micron 30×4.6 mm C18 column and a 2 mL/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.3 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.

Microwave experiments were carried out using a Biotage Initiator™, which uses a single-mode resonator and dynamic field tuning. Temperatures from 40-250° C. can be achieved, and pressures of up to 20 bars can be reached. A facility exists to apply air cooling during the irradiation.

Preparative HPLC purification was carried out using either a C18-reverse-phase column from Genesis (C18) or a C6-phenyl column from Phenomenex (C6-phenyl) (100×22.5 mm i.d. with 7 micron particle size, UV detection at 230 or 254 nm, flow 5-15 mL/min), eluting with gradients from 100-0 to 0-100% water/acetonitrile or water/methanol containing 0.1% formic acid. Fractions containing the required product (identified by LCMS analysis) were pooled, the organic fraction removed by evaporation, and the remaining aqueous fraction lyophilised, to give the product.

Alternatively, preparative HPLC purification was carried out using an mass directed automated purification system (MDAP) using an Agilent 1260 infinity purifications system with an Agilent 6100 series single Quadrupole LC/MS. The column used was an X-Select C18 CSH 5 μm, 30×150 mm. Chromatography was carried out using gradients from 10-95% water/acetonitrile containing 0.1% formic acid centered around a focused gradient.

Compounds which required column chromatography were purified manually or fully automatically using either a Biotage SP1™ Flash Purification system with Touch Logic Control™ or a Combiflash Companion® with pre-packed silica gel Isolute® SPE cartridge, Biotage SNAP cartridge or Redisep® Rf cartridge respectively.

Compounds have been named using Autonom2000 within ISISDraw.

Abbreviations:

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCE 1,2-Dichloroethane

DCM Dichloromethane

DIBAL Diisobutylaluminium hydride

DMAP 4-Dimethylaminopyridine

DME Dimethoxymethane

DMF N,N-Dimethylformamide

DMSO Dimethylsulfoxide

EDAC N-(3-Dimethylaminopropyl)-N′ethylcarbodiimide

Hydrochloride

HOBT 1-Hydroxybenzotriazole

IMS Industrial methylated spirits

SCX Strong cation exchange cartridge

TBME Methyl tert-butyl ether

TFA Trifluoroacetic acid

THF Tetrahydrofuran

Example 1: (1aR,7bS)-5-[2-(2-Diethylaminomethylcyclopropyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Lithium hydroxide (0.052 g) was added to a solution of methyl (1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 1, 0.062 g) in a mixture of dioxane (3 mL) and water (1 mL) and the resultant mixture was irradiated in the microwave at 150° C. with air cooling for 20 minutes. After cooling, the solution was acidified by addition of aqueous citric acid solution (10%) and the resultant mixture was extracted with DCM, dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 20-98% to afford (1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid (0.041 g) as a white solid.

¹H NMR (CDCl₃) δ: 8.11-8.03 (1H, m), 7.11-7.06 (1H, m), 7.04-6.94 (2H, m), 6.84 (1H, td), 4.41 (1H, dd), 3.83 (1H, d), 3.23-2.94 (6H, m), 2.15-2.05 (1H, m), 1.92-1.85 (1H, m), 1.84-1.74 (1H, m), 1.74-1.65 (1H, m), 1.51-1.41 (1H, m), 1.26-1.16 (7H, m), 1.07-0.92 (2H, m).

LCMS (Method C) r/t 3.23 (M−H) 487.

Examples 2 and 3

Separation of enantiomers from Example 1.

Sample from Example 1 was subjected to chiral separation using a ChiralPak IA column, 10 mm×250 mm, particle size 5 micron. Eluting solvent: 55% heptane, 27% Ethanol and 18% DCM.

Example 2

First eluting enantiomer: r/t on analytical column (4.6 mm×250 mm): 12.73 minutes as a white solid.

¹H NMR (DMSO-d₆) δ: 8.03 (1H, dd), 7.23 (1H, td), 7.17 (1H, d), 7.03 (1H, d), 6.70 (1H, d), 4.23 (1H, d), 3.64 (1H, d), 3.07-2.96 (3H, m), 2.95-2.86 (2H, m), 2.32-2.21 (1H, m), 1.93-1.85 (1H, m), 1.77-1.59 (2H, m), 1.49-1.41 (1H, m), 1.37-1.18 (2H, m), 1.01 (6H, t), 0.95-0.88 (1H, m), 0.71-0.65 (1H, m).

LCMS (Method C) r/t 3.25 (M−H) 487.

Example 3

Second eluting enantiomer: r/t on analytical column (4.6 mm×250 mm): 22.3 minutes as a beige solid which was triturated with ether plus few drops of acetonitrile to give a white solid.

¹H NMR (DMSO-d₆) δ: 8.01 (1H, dd), 7.26-7.12 (2H, m), 7.01 (1H, d), 6.70 (1H, d), 4.22 (1H, d), 3.63 (1H, d), 3.07-2.84 (5H, m), 2.34-2.23 (1H, m), 1.91-1.81 (1H, m), 1.76-1.60 (2H, m), 1.46-1.37 (1H, m), 1.31-1.19 (2H, m), 1.01 (6H, t), 0.95-0.86 (1H, m), 0.75-0.70 (1H, m).

LCMS (Method C) r/t 3.23 (M+H) 489.

Example 4: (1aR,7bS)-5-{4-Fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 1, starting from methyl (1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 14), as a white solid.

¹H NMR (CDCl₃) δ: 8.02-7.92 (1H, m), 7.14-7.07 (1H, m), 7.02-6.91 (2H, m), 6.77 (1H, ddd), 4.40 (1H, d), 3.82 (1H, dd), 3.36-3.02 (6H, m), 2.34-2.24 (1H, m), 2.08-1.97 (4H, m), 1.94-1.76 (2H, m), 1.74-1.65 (1H, m), 1.48-1.37 (1H, m), 1.21-1.09 (1H, m), 1.07-0.91 (2H, m).

LCMS (Method C) r/t 3.21 (M−H) 485.

Example 5: (1aR,7bS)-5-[2-(3-Diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

A mixture of methyl (1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 15, 0.133 g) and lithium hydroxide monohydrate (0.168 g) in water (1 mL) and dioxane (3 mL) was irradiated in the microwave at 130° C. for 40 minutes. After cooling, the mixture was diluted with methanol and acidified by addition of formic acid (10%). The volatiles were removed by evaporation and the residue was triturated with 15% methanol in DCM. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-30% to give (1aR,7bS)-5-{2-[3-(diethylamino)-2,2-dimethylpropyl]-4-fluorophenyl}sulfonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.091 g) as a white solid.

¹H NMR (DMSO-d₆) δ: 7.97-7.91 (1H, m), 7.20-7.12 (2H, m), 7.01 (1H, d), 6.61 (1H, d), 4.21 (1H, d), 3.63 (1H, d), 3.04 (2H, s), 2.90-2.77 (4H, m), 2.65 (2H, br s), 1.90-1.82 (1H, m), 1.75-1.66 (1H, m), 1.08 (6H, t), 0.97-0.86 (7H, m), 0.76-0.70 (1H, m).

LCMS (Method C) r/t 3.34 (M−H) 503.

Example 6: (1aR,7bS)-5-[4-Fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 5, starting from methyl (1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 21), as a white solid.

¹H NMR (DMSO-d₆) δ: 7.80 (1H, dd), 7.27 (1H, dd), 7.17-7.11 (1H, m), 7.08 (1H, d), 7.00 (1H, d), 4.15 (1H, d), 3.61 (1H, d), 3.57-3.46 (1H, m), 3.25-2.87 (6H, m), 2.19-2.03 (1H, m), 1.93-1.85 (1H, m), 1.84-1.65 (2H, m), 0.95-0.86 (1H, m), 0.77-0.68 (1H, m).

LCMS (Method C) r/t 3.05 (M−H) 445.

Example 7: (1aR,7bS)-5-[4-Fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 5, starting from methyl (1aR,7bS)-5-[4-fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 27), as a white solid.

¹H NMR (DMSO-d₆) δ: 7.80 (1H, dd), 7.27 (1H, dd), 7.17-7.11 (1H, m), 7.08 (1H, d), 7.00 (1H, d), 4.15 (1H, d), 3.60-3.50 (2H, m), 3.25-2.87 (6H, m), 2.19-2.03 (1H, m), 1.93-1.85 (1H, m), 1.84-1.65 (2H, m), 0.95-0.86 (1H, m), 0.77-0.68 (1H, m).

LCMS (Method C) r/t 3.04 (M−H) 445.

Example 8: (1aR,7bS)-5-{4-Fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 1, starting from methyl (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)pyrrolidin-3-ylmethyl]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 33), as a white solid.

¹H NMR (DMSO-d₆) δ: 7.92-7.86 (1H, m), 7.25 (1H, dd), 7.17 (1H, td), 7.07 (1H, d), 6.97 (1H, d), 4.18 (1H, d), 3.62 (1H, d), 3.60-3.50 (1H, m), 3.40-3.06 (7H, m), 2.97-2.83 (1H, m), 2.17-2.04 (1H, m), 1.93-1.84 (1H, m), 1.76-1.67 (1H, m), 1.66-1.53 (1H, m), 1.24 (6H, d), 0.96-0.87 (1H, m), 0.74 (1H, q).

LCMS (Method C) r/t 3.17 (M−H) 517.

Example 9: (1aR,7bS)-5-[2-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 1, starting from methyl (1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 34), as a white solid.

¹H NMR (CDCl₃) δ: 8.21 (1H, br s), 8.12-8.05 (1H, m), 7.17-7.12 (1H, m), 7.11-7.05 (1H, m), 7.03-6.96 (1H, m), 6.91-6.85 (1H, m), 4.45 (1H, d), 3.91-3.81 (1H, m), 3.63-3.30 (3H, m), 3.30-3.02 (3H, m), 2.98-2.85 (1H, m), 2.57-2.44 (1H, m), 2.30-2.17 (1H, m), 2.00 (1H, s), 1.94-1.85 (2H, m), 1.85-1.76 (2H, m), 1.76-1.67 (1H, m), 1.06-0.94 (2H, m).

LCMS (Method C) r/t 3.18 (M−H) 485.

Examples 10 and 11: (1aR,7bS)-5-[2-((Z)-1-Azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid and (1aR,7bS)-5-[2-((E)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Lithium hydroxide (0.08 g) was added to a solution of methyl (1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (mixture of E and Z isomers, Intermediate 39, 0.095 g) in a mixture of dioxane (3 mL) and water (1 mL) and the resultant mixture was irradiated in the microwave at 150° C. with air cooling for 20 minutes. After cooling, the solution was acidified by addition of aqueous citric acid solution (10%) and the mixture was extracted with DCM, dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the resultant residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 20-98% to give:

Example 10

(1aR,7bS)-5-[2-((Z)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid as the first eluting isomer (0.017 g), as a white solid.

Structure confirmed by nOesy NMR experiments.

¹H NMR (DMSO-d₆) δ: 7.92 (1H, dd), 7.27-7.18 (2H, m), 6.99 (1H, d), 6.91-6.86 (1H, m), 6.82 (1H, d), 4.17 (1H, d), 4.01 (2H, s), 3.61-3.14 (5H, m), 2.74-2.68 (1H, m), 2.12-1.89 (4H, m), 2.12-1.81 (1H, m), 1.74-1.65 (1H, m), 0.93-0.85 (1H, m), 0.76-0.69 (1H, m).

LCMS (Method C) r/t 3.19 (M−H) 483.

Example 11

(1aR,7bS)-5-[2-((E)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid as the second eluting isomer (0.011 g), as a white solid.

Structure confirmed by nOesy NMR experiments.

¹H NMR (DMSO-d₆) δ: 8.13 (1H, dd), 7.29 (1H, td), 7.01 (1H, dd), 6.92 (1H, d,), 6.74 (1H, br m), 6.52 (1H, d), 4.21 (1H, d), 4.01 (2H, br s), 3.53 (1H, d), 3.19-3.04 (4H, m), 2.65-2.61 (1H, m), 1.85-1.77 (1H, m), 1.73-1.60 (3H, m), 1.52-1.34 (2H, m), 0.90-0.80 (1H, m), 0.70-0.64 (1H, m).

LCMS (Method C) r/t 3.27 (M−H) 483.

Examples 12 and 13: (1aR,7bS)-5-{2-[(E)-(1-Ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid and (1aR,7bS)-5-{2-[(Z)-(1-Ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

A mixture of methyl (1aR,7bS)-5-{2-[(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (mixture of E and Z isomers, Intermediate 41, 0.372 g) and lithium hydroxide monohydrate (0.312 g) in water (2 mL) and dioxane (8 mL) was heated at 100° C. for 6 hours. After cooling, the volatiles were removed by evaporation and the residue was treated with citric acid (10%). The mixture was extracted with DCM and the organic layer was washed with brine, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by MDAP followed by HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 35-55% to give:

Example 12

(1aR,7bS)-5-{2-[(E)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid as the first eluting isomer (0.06 g).

¹H NMR (DMSO-d₆) δ: 8.12 (1H, dd), 7.35-7.24 (2H, m), 7.05-7.01 (2H, m), 6.93 (1H, d), 4.22 (1H, d), 3.85-3.73 (2H, m), 3.59 (2H, d), 3.17-3.08 (3H, m), 2.46-2.36 (2H, m), 1.91-1.82 (1H, m), 1.76-1.61 (3H, m), 1.43-1.34 (3H, m), 0.94-0.86 (1H, m), 0.76-0.69 (1H, m).

LCMS (Method C) r/t 3.42 (M−H) 485.

Example 13

(1aR,7bS)-5-{2-[(Z)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid as the second eluting isomer (0.016 g).

¹H NMR (DMSO-d₆) δ: 7.65-7.58 (1H, m), 7.22-7.15 (1H, m), 7.14-7.06 (3H, m), 6.98 (1H, d), 4.15 (1H, d), 3.69 (2H, br s), 3.56 (1H, d), 3.23-3.09 (2H, br m), 2.98 (2H, br s), 2.47-2.38 (2H, m), 2.08-1.86 (3H, m), 1.76-1.68 (1H, m), 1.13 (3H, t), 0.98-0.88 (1H, m), 0.74 (1H, q).

LCMS (Method C) r/t 3.51 (M−H) 485.

Examples 14 and 15: (1aR,7bS)-5-[2-((R)-1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid and (1aR,7bS)-5-[2-((S)-1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

A mixture of methyl (1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 45, 0.071 g) and lithium hydroxide monohydrate (0.059 g) in dioxane (5 mL) and water (2 mL) was stirred and heated at 100° C. for 25 hours. Further lithium hydroxide monohydrate (0.116 g) was added and the mixture was heated at 100° C. for a further 18 hours. After cooling, the volatiles were removed in vacuo and the residue was acidified by addition of aqueous citric acid solution (10%) and saturated with sodium chloride. The mixture was extracted with DCM and the organic layer was dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18), eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 25-60%, to give a mixture of (1aR,7bS)-5-[2-((R)-1-ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid and (1aR,7bS)-5-[2-((S)-1-ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.032 g) as a white solid.

This mixture was subjected to chiral separation using a ChiralPak IC column, 10 mm×250 mm, particle size 5 micron. Eluting solvent: ethanol

Example 14

First eluting enantiomer: r/t on analytical column (4.6 mm×250 mm): 18.21 minutes.

¹H NMR (DMSO-d₆) δ: 8.01-7.91 (1H, m), 7.26-7.18 (2H, m), 7.10-7.00 (2H, m), 4.20 (1H, d), 3.61 (1H, d), 3.24-2.89 (4H, m), 2.86-2.77 (1H, m), 2.76-2.56 (2H, m), 1.94-1.85 (2H, m), 1.81-1.54 (4H, m), 1.30-1.14 (5H, m), 0.97-0.87 (1H, m), 0.77-0.68 (1H, m).

LCMS (Method C) r/t 3.22 (M−H) 487.

Example 15

Second eluting enantiomer: r/t on analytical column (4.6 mm×250 mm): 29.57 minutes.

¹H NMR (DMSO-d₆) δ: 8.01-7.91 (1H, m), 7.26-7.18 (2H, m), 7.10-7.00 (2H, m), 4.20 (1H, d), 3.61 (1H, d), 3.24-2.89 (4H, m), 2.79-2.58 (3H, m), 1.95-1.86 (1H, m), 1.86-1.64 (4H, m), 1.62-1.45 (1H, m), 1.30-1.14 (5H, m), 0.97-0.87 (1H, m), 0.77-0.68 (1H, m).

LCMS (Method C) r/t 3.23 (M−H) 487.

Example 16: (1aR,7bS)-5-{2-[2-((S)-1-Ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Lithium hydroxide (0.11 g) was added to a solution of methyl (1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 53, 0.13 g) in a mixture of dioxane (6 mL) and water (2 mL) and the resultant mixture was irradiated in the microwave at 150° C. with air cooling for 20 minutes. After cooling, the mixture was acidified by addition of aqueous formic acid and extracted with DCM, dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by MDAP to give (1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.078 g) as a glass.

¹H NMR (DMSO-d₆) δ: 7.91-7.85 (1H, m), 7.32 (1H, dd), 7.15 (1H, td), 7.06 (1H, d), 6.97 (1H, d), 4.17 (1H, d), 3.70-3.46 (4H, m), 3.18-2.94 (4H, m), 2.28-2.15 (1H, m), 2.10-1.93 (4H, m), 1.91-1.80 (2H, m), 1.75-1.64 (1H, m), 1.33-1.25 (3H, m), 0.96-0.86 (1H, m), 0.75-0.69 (1H, m).

LCMS (Method C) r/t 3.27 (M−H) 487.

Example 17: (1aR,7bS)-5-{4-Fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 1, starting from methyl (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 60), as white solid.

¹H NMR (DMSO-d₆) δ: 7.85 (1H, dd), 7.24 (1H, dd), 7.15 (1H, td), 7.06 (1H, d), 6.97-6.90 (1H, m), 4.18 (1H, d), 3.68-3.56 (3H, m), 3.21-2.81 (10H, m), 2.21-2.06 (1H, m), 1.92-1.84 (1H, m), 1.76-1.66 (1H, m), 1.64-1.51 (1H, m), 0.96-0.86 (1H, m), 0.74 (1H, q).

LCMS (Method C) r/t 3.05 (M−H) 489.

Examples 18 and 19: (1aR,7bS)-5-[2-((Endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid and (1aR,7bS)-5-[2-((exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 1, starting from a mixture of exo and endo methyl (1aR,7bS)-5-[2-(8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 62). The isomers were separated by preparative HPLC (C18).

Example 18: (1aR,7bS)-5-[2-((Endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

First Eluting Isomer

¹H NMR (DMSO-d₆) δ: 7.86 (1H, dd), 7.22-7.11 (2H, m), 7.05 (1H, d), 6.99-6.92 (1H, m), 4.19 (1H, d), 3.89-3.80 (2H, br s), 3.61 (1H, d), 3.18-3.03 (3H, m), 2.98-2.87 (2H, m), 2.35-2.12 (4H, m), 2.03-1.95 (2H, m), 1.92-1.83 (1H, m), 1.74-1.66 (1H, m), 1.49 (2H, dd), 1.21 (3H, t), 0.94-0.86 (1H, m), 0.73 (1H, q).

LCMS (Method C) r/t 3.33 (M−H) 513.

Example 19: (1aR,7bS)-5-[2-((Exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Second Eluting Isomer

¹H NMR (DMSO-d₆) δ: 8.06 (1H, dd), 7.28 (1H, d), 7.19 (1H, td), 6.98 (1H, d), 6.68 (1H, d), 4.22 (1H, d), 3.73-3.58 (3H, m), 2.95-2.75 (4H, m), 2.38-2.22 (1H, m), 2.01-1.91 (2H, m), 1.89-1.81 (1H, m), 1.76-1.40 (7H, m), 1.26-1.16 (3H, m), 0.93-0.85 (1H, td), 0.77-0.71 (1H, m).

LCMS (Method C) r/t 3.35 (M−H) 513.

Example 20: (1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

To a solution of methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 67, 0.34 g) in 1,4-dioxane (20 mL) and water (10 mL) under an atmosphere of nitrogen was added lithium hydroxide monohydrate (0.248 g). The resulting solution was heated at reflux for 18 hours. After cooling, the volatiles were removed by evaporation and the residue was diluted with water (30 mL) and the pH adjusted to 4 by addition of an aqueous solution of formic acid. The mixture was extracted with ethyl acetate and THF (1:1 mixture) and the combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by HPLC to give (1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.106 g) as an off-white solid.

¹H NMR (CDCl₃) δ: 7.65 (1H, d), 7.58-7.48 (1H, m), 7.26 (1H, m), 7.16-7.10 (1H, m), 6.87 (1H, ddd), 6.71 (1H, dt), 5.99-5.89 (1H, m), 4.28 (1H, d), 4.14-3.94 (1H, m), 3.81-3.58 (3H, m), 3.49-3.22 (2H, m), 3.04 (1H, dd), 2.20-2.07 (1H, m), 2.06 (1H, m), 1.92-1.82 (1H, m), 1.68-1.59 (1H, m), 1.26 (3H, s), 1.09-1.01 (1H, m), 0.96-0.87 (1H, m).

LCMS (Method C) r/t 3.06 (M+H) 503

Example 21: (1aR,7bS)-5{4-Fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 20, starting from methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 71), as an off-white solid.

¹H NMR (DMSO-d₆) δ: 7.63 (1H, d), 7.45-7.37 (1H, m), 7.18-7.10 (2H, m), 6.84 (1H, dt), 6.73 (1H, dd), 6.06-5.96 (1H, m), 4.27 (1H, d), 4.08-3.99 (1H, m), 3.98-3.90 (1H, m), 3.69 (1H, d), 3.50-3.40 (1H, m), 3.35-3.11 (4H, m), 2.16-2.03 (2H, m), 1.93-1.84 (2H, m), 1.85-1.74 (1H, m), 1.69-1.59 (1H, m), 1.08-1.00 (1H, m), 0.97-0.88 (1H, m).

LCMS (Method C) r/t 3.06 (M+H) 503.

Example 22: (1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 20, starting from methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 72), as a light yellow solid.

¹H NMR (DMSO-d₆) δ: 7.58 (1H, m), 7.28 (1H, d), 7.18 (1H, dt), 7.13 (1H, dd), 7.07 (1H, d), 6.90 (1H, d), 6.22-6.12 (1H, m), 4.63 (1H, m), 4.12 (1H, d), 3.78-3.57 (1H, m), 3.54 (1H, d), 3.11-2.84 (5H, m), 1.93-1.84 (1H, m), 1.73-1.64 (1H, m), 1.64-1.50 (3H, m), 1.12 (3H, s), 0.94-0.84 (1H, m), 0.73-0.65 (1H, m).

LCMS (Method C) r/t 3.16 (M+H) 517.

Example 23: (1aR,7bS)-5-[2-(3-Ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

A suspension of methyl (1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 73, 0.247 g) and lithium hydroxide monohydrate (0.214 g) in dioxane (6 mL) and water (3 mL) was heated at 80° C. for 18 hours under an atmosphere of nitrogen. After cooling, the volatiles were removed in vacuo and the residue was acidified by addition of aqueous citric acid solution (10%). The mixture was extracted with DCM and the organic layer was dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by MDAP to give (1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.13 g) as a white solid.

¹H NMR (DMSO-d₆) δ: 8.08 (1H, dd), 7.28-7.15 (2H, m), 7.06 (1H, d), 6.89 (1H, d), 4.20 (1H, d), 3.90-3.80 (2H, m), 3.65 (1H, d), 3.40-3.30 (2H, m), 3.28-3.18 (2H, m), 2.51-2.45 (1H, m), 2.38-2.27 (2H, m), 1.93-1.85 (1H, m), 1.77-1.68 (1H, m), 1.34 (3H, t), 0.97-0.88 (1H, m), 0.78-0.72 (1H, m).

LCMS (Method C) r/t 3.17 (M−H) 471.

Example 24: (1aR,7bS)-5-{4-Fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 1, starting from methyl (1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 78), as an off-white powder (0.028 g).

¹H NMR (DMSO-d₆) δ: 7.49 (1H, dd), 7.21-7.06 (4H, m), 6.98 (1H, dd), 5.96-5.89 (1H, m), 4.12 (1H, d), 3.94-3.80 (1H, m), 3.47 (1H, d), 3.16 (2H, t), 2.35-2.23 (1H, m), 2.03-1.85 (3H, m), 1.77-1.65 (2H, m), 0.95-0.86 (1H, m), 0.73-0.64 (1H, m).

LCMS (Method C) r/t 3.31 (M−H) 457.

Example 25: (1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-((S)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 20, starting from methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-((S)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 82), as an off-white solid.

¹H NMR (CDCl₃) δ: 7.64 (1H, d), 7.52 (1H, dd), 7.21 (1H, d), 7.12 (1H, d), 6.86 (1H, dt), 6.71 (1H, dd), 5.98-5.89 (1H, m), 4.26 (1H, d), 3.98-3.83 (1H, m), 3.71 (1H, d), 3.64-3.48 (5H, m), 3.32-3.19 (1H, m), 3.18-3.06 (1H, m), 2.66-2.54 (1H, m), 2.20-2.08 (1H, m), 1.91-1.74 (2H, m), 1.67-1.59 (1H, m), 1.06-0.98 (1H, m), 0.95-0.88 (1H, m).

LCMS (Method C) r/t 3.13 (M+H) 503.

Example 26: (1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 20, starting from methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 85), as a white solid.

¹H NMR (CDCl₃) δ: 7.65 (1H, d), 7.50 (1H, d), 7.21 (1H, d), 7.14 (1H, d), 6.85 (1H, dt), 6.71 (1H, dd), 5.98-5.88 (1H, m), 4.27 (1H, d), 4.19 (1H, m), 3.84-3.70 (1H, m), 3.69 (1H, d), 3.63-6.43 (4H, m), 3.24-3.12 (1H, m), 3.12-3.00 (1H, m), 2.66-2.53 (1H, m), 2.24-2.11 (1H, m), 1.92-1.84 (1H, m), 1.84-1.73 (1H, m), 1.68-1.59 (1H, m), 1.09-1.02 (1H, m), 0.96-0.88 (1H, m).

LCMS (Method C) r/t 3.13 (M+H) 503.

Example 27: (1aR,7bS)-5-(4-Fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 20, starting from methyl (1aR,7bS)-5-[N-(4-fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzene-sulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 86), as a white solid.

¹H NMR (CDCl₃) δ: 7.63 (1H, d), 7.48-7.40 (1H, m), 7.19 (1H, d), 7.11 (1H, d), 6.83 (1H, dt), 6.70 (1H, dd), 5.97-5.88 (1H, m), 4.26 (1H, d), 4.02-3.84 (1H, m), 3.70 (1H, d), 3.69-3.11 (5H, m), 2.44-2.32 (1H, m), 2.08-1.98 (2H, m), 1.91-1.83 (1H, m), 1.67-1.59 (1H, m), 1.21 (3H, s), 1.19 (3H, s), 1.07-0.98 (1H, m), 0.95-0.87 (1H, m).

LCMS (Method C) r/t 3.31 (M+H) 531.

Example 28: (1aR,7bS)-5-(4-Fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 20, starting from methyl (1aR,7bS)-5-[N-(4-fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzene-sulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 87), as a white solid.

¹H NMR (CDCl₃) δ: 7.63 (1H, d), 7.47-7.39 (1H, m), 7.19 (1H, d), 7.12 (1H, d), 6.83 (1H, dt), 6.70 (1H, dd), 5.98-5.88 (1H, m), 4.27 (1H, d), 4.19 (1H, m), 3.67 (1H, d), 3.58-3.13 (5H, m), 2.43-2.31 (1H, m), 2.10-1.99 (2H, m), 1.92-1.83 (1H, m), 1.67-1.58 (1H, m), 1.22 (3H, s), 1.18 (3H, s), 1.10-1.02 (1H, m), 0.96-0.87 (1H, m).

LCMS (Method C) r/t 3.31 (M+H) 531.

Example 29: (1aR,7bS)-5-[4-Fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

A mixture of methyl (1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 88, 0.09 g) and lithium hydroxide monohydrate (0.076 g) in dioxane (7 mL) and water (3 mL) was heated at 80° C. under an atmosphere of nitrogen for 20 hours. Further lithium hydroxide monohydrate (0.152 g) and water (4 mL) were added and the temperature raised to 100° C. After 6.5 hours stirring at that temperature, the reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was acidified by addition of aqueous citric acid solution (10%) and the mixture was extracted with DCM. The organic layer was dried (Na₂SO₄), filtered and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 25-40% to give (1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid (0.031 g) as a white solid.

¹H NMR (DMSO-d₆) δ: 7.98-7.90 (1H, m), 7.22-7.15 (2H, m), 7.03 (1H, dd), 6.94 (1H, t), 4.20-4.04 (2H, m), 3.60 (1H, t), 3.45-2.97 (4H, m), 2.76-2.63 (1H, m), 2.62-2.50 (1H, m), 2.25-1.82 (6H, m), 1.76-1.63 (2H, m), 1.47-1.35 (1H, m), 0.94-0.85 (1H, m), 0.75-0.67 (1H, m).

LCMS (Method C) r/t 3.16 (M+H) 487.

Example 30: (1aR,7bS)-5-{2-[((S)-1-Ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 1, starting from methyl (1aR,7bS)-5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 96), as a white solid.

¹H NMR (DMSO-d₆) δ: 9.55 (1H, s), 7.59 (1H, dd), 7.34 (1H, dd), 7.20-7.10 (2H, m), 7.04 (1H, d), 4.49-4.41 (1H, m), 4.13 (1H, d), 3.86 (1H, d), 3.72 (1H, d), 3.62 (1H, d), 3.59-3.47 (1H, m), 3.31 (1H, d), 3.20-3.07 (2H, m), 3.06-2.95 (2H, m), 2.46-2.31 (1H, m), 1.99-1.90 (2H, m), 1.78-1.68 (1H, m), 1.20 (3H, t), 0.99-0.92 (1H, m), 0.81-0.74 (1H, m).

LCMS (Method C) r/t 3.01 (M−H) 516.

Example 31: (1aR,7bS)-5-[2-((3R)-1-Ethylpyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid

Prepared by proceeding in a similar manner to Example 16, starting from methyl (1aR,7bS)-5-[2-((3R)-1-ethylpyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 102) as a white solid

¹H NMR (DMSO-d₆) δ: 7.77 (1H, dd), 7.53 (1H, td), 7.38 (1H, d), 7.31 (1H, t), 7.11-6.99 (2H, m), 4.16 (1H, d), 3.64-3.52 (2H, m), 3.24-2.92 (8H, m), 2.29-2.16 (1H, m), 1.93-1.85 (1H, m), 1.74-1.62 (2H, m), 1.22 (3H, t), 0.95-0.88 (1H, m), 0.73 (1H, q).

LCMS (Method C) r/t 3.11 (M−H) 455.

Example 32: (1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)aminomethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid-formic acid (1:1)

Methyl (1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)aminomethyl]-4-fluoro-benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 106, 0.207 g) and lithium hydroxide monohydrate (0.164 g) were suspended in dioxane (12 mL) and water (6 mL) and the mixture was heated at 100° C. for 5.5 hours under an atmosphere of nitrogen. After cooling, the mixture was acidified to pH3 by addition of aqueous citric acid solution (10%) and extracted with DCM. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 25-60%. The resultant solid was dissolved in dioxane (5 mL) and water (5 mL), treated with lithium hydroxide monohydrate (0.164 g) and heated at 80° C. for 2 days. After cooling, the mixture was acidified to pH3 by addition of aqueous citric acid solution (10%) and extracted with DCM. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 25-60% to give (1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)-aminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid-formic acid (1:1) (0.052 g) as a white solid.

¹H NMR (DMSO-d₆) δ: 8.78 (1H, q), 8.14 (1H, s), 7.89-7.82 (1H, m), 7.19 (1H, td), 7.12 (1H, dt), 7.02 (1H, dd), 6.75 (1H, dd), 4.74 (2H, d), 4.19 (1H, d), 3.62 (1H, d), 3.50-3.15 (5H, m), 3.10 (2H, q), 2.35-2.23 (1H, m), 2.10-1.99 (1H, m), 1.91-1.81 (1H, m), 1.75-1.67 (1H, m), 1.20 (3H, t), 0.93-0.86 (1H, m), 0.75-0.70 (1H, m).

LCMS (Method C) r/t 3.01 (M−H) 516.

Example 33: (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluoro-benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid-formic acid (1:1)

A mixture of methyl (1aR,7bS)-5-(2-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 115, 0.048 g) and lithium hydroxide (0.033 g) in dioxane (1 mL) and water (0.4 mL) was irradiated in the microwave at 150° C. for 30 minutes. After cooling, the volatiles were removed by evaporation and the residue was partitioned between 10% aqueous citric acid and DCM. The combined aqueous and organic layers were loaded onto an SCX column and the column was washed with methanol. The product was eluted off the column with 2M ammonia in methanol. The resultant material was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic, with a gradient of 20-98% to give (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid-formic acid (1:1) (0.019 g) as a white solid.

¹H NMR (DMSO-d₆) δ: 8.13 (1H, s), 7.81 (1H, dd), 7.22 (1H, dd), 7.10 (1H, dt), 7.00 (1H, d), 6.88 (1H, d), 4.13 (1H, d), 3.57 (1H, d), 3.52-3.45 (1H, m), 3.18-3.03 (4H, m), 2.96-2.69 (6H, m), 2.16-2.05 (1H, m), 1.87-1.79 (1H, m), 1.79-1.70 (1H, m), 1.69-1.61 (1H, m), 1.11 (3H, t), 0.90-0.82 (1H, m), 0.72-0.66 (1H, m).

LCMS (Method C) r/t 2.62 (M+H) 504.

Intermediate 1: Methyl (1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate

A mixture of methyl (1aR,7bS)-5-{N-[4-fluoro-2-(2-methanesulfonyloxymethylcyclopropyl)-benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 2, 0.227 g) and diethylamine (1 mL) in DCE (2.5 mL) was heated at 45° C. in a sealed vial for 6 hours. The volatiles were removed by evaporation and the residue was purified by chromatography on silica, eluting with a mixture of methanol and ethyl acetate, with a gradient of 0-20% to give methyl(1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.063 g) as a white solid.

LCMS (Method A) r/t 2.49 (M+H) 503.

Intermediate 2: Methyl (1aR,7bS)-5-{N-[4-fluoro-2-(2-methanesulfonyloxymethyl-cyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

A solution of methanesulfonyl chloride (0.12 g) in DCM (2 mL) was added to a mixture of methyl (1aR,7bS)-5-{N-[4-fluoro-2-(2-hydroxymethylcyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 3, 0.43 g), DMAP (0.01 g) and triethylamine (0.24 mL) in DCM (15 mL). The mixture was stirred at room temperature for 30 minutes and then the volatiles were removed by evaporation. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-80%, to give methyl 1aR,7bS)-5-{N-[4-fluoro-2-(2-methanesulfonyloxymethylcyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.49 g) as a white solid.

LCMS (Method A) r/t 3.49 (M+Na) 606.

Intermediate 3: Methyl (1aR,7bS)-5-{N-[4-fluoro-2-(2-hydroxymethylcyclopropyl)-benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Concentrated hydrochloric acid (20 mL) was added to a solution of methyl (1aR,7bS)-5-{N-[4-fluoro-2-(2-methoxymethylcyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 4, 0.97 g) in methanol (5 mL) and dioxane (10 mL). The mixture was stirred at 20° C. for 5 hours then the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate and the combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100%, to give methyl (1aR,7bS)-5-{N-[4-fluoro-2-(2-hydroxymethylcyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (1.01 g) as a colourless oil.

LCMS (Method A) r/t 3.20 (M+Na) 528.

Intermediate 4: Methyl (1aR,7bS)-5-{N-[4-fluoro-2-(2-methoxymethoxymethyl-cyclopropyl)-benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

A mixture of methyl chloroformate (1.03 g) in DCM (20 mL) was slowly added to a solution of methyl (1aR,7bS)-5-[4-fluoro-2-(2-methoxymethoxymethylcyclopropyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 5, 1.07 g) and pyridine (15 mL) in DCM (10 mL) at 0° C. under an atmosphere of nitrogen. The mixture was stirred at 0° C. for 15 minutes and then at 20° C. Further methyl chloroformate (0.5 g and 0.28 g) were added after 3 hours and 4 hours stirring, respectively. Stirring at room temperature was continued for 1 hour then the volatiles were removed by evaporation. The residue was partitioned between DCM and water and the organic layer was dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60%, to give methyl (1aR,7bS)-5-{N-[4-fluoro-2-(2-methoxymethoxy-methylcyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (1.2 g) as a colourless oil.

LCMS (Method A) r/t 3.69 (M+Na) 572.

Intermediate 5: Methyl (1aR,7bS)-5-[4-fluoro-2-(2-methoxymethoxymethylcyclopropyl)-benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A mixture of methyl (1aR,7bS)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 6, 0.6 g), 2-[2-(methoxymethoxymethyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 7, 0.38 g), tris-(dibenzylideneacetone)dipalladium (0.12 g), tri-tert-butylphosphonium tetrafluoroborate (0.05 g) and cesium carbonate (1.71 g) in dioxane (10 mL) and water (3 mL) was degassed with a stream of argon and irradiated in the microwave at 150° C. for 45 minutes. The reaction was repeated a further two times using the same amount of reagents under the reaction conditions described above. The combined reaction mixtures were partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate and the combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-50%, to give methyl (1aR,7bS)-5-[4-fluoro-2-(2-methoxymethoxymethylcyclopropyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (1.12 g) as a gum.

LCMS (Method A) r/t 3.79 (M+Na) 514.

Intermediate 6: Methyl (1aR,7bS)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

2-Bromo-4-fluorobenzenesulfonyl chloride (4.48 g) was added portionwise to a stirred solution of methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 2.99 g) and pyridine (15 mL) in DCM (25 mL) at 0° C. The mixture was stirred at 0° C. under an atmosphere of nitrogen for 10 minutes and then at room temperature for 2 hours. The volatiles were removed by evaporation and the residue was partitioned between DCM and 1M aqueous hydrochloric acid solution. The aqueous phase was extracted with DCM and the organic layer was dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-50%, to give methyl (1aR,7bS)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (6.02 g) as a white solid.

¹H NMR (CDCl₃) δ: 9.31 (1H, br, s), 8.14 (1H, dd), 7.41 (1H, dd), 7.17 (1H, d), 7.11 (1H, ddd), 7.06 (1H, d), 4.34 (1H, dd), 3.90 (3H, s), 3.80 (1H, dd), 1.94-1.85 (1H, m), 1.75-1.67 (1H, m), 1.01 (2H, m).

Intermediate 7: 2-[2-(Methoxymethoxymethyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Diiodomethane (5.5 mL) was added to a mixture of diethylzinc (1.1M in toluene, 52 mL) in DCM (16 mL) at 0° C. under an atmosphere of nitrogen. The mixture was stirred at 0° C. for 10 minutes then a solution of 2-((Z)-3-methoxymethoxyprop-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (5.18 g) in DCM (20 mL) was added over 10 minutes. The mixture was stirred at 0° C. for 15 minutes, then at 20° C. for 16 hours. The resultant mixture was cooled to 0° C. and added by a cannula to a solution of diiodomethane (3.3 mL) and diethylzinc (1.1M in toluene, 31 mL) in DCM (10 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes, then at 20° C. for 16 hours. The mixture was poured into a saturated solution of ammonium chloride and extracted with ethyl acetate, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-30%, to give 2-[2-(methoxymethoxymethyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colourless oil (3.03 g).

¹H NMR (CDCl₃) δ: 4.67-4.60 (2H, m), 3.68 (1H, dd), 3.48 (1H, dd), 3.38 (3H, s), 1.47-1.36 (1H, m), 1.22 (12H, d), 0.92-0.85 (1H, m), 0.56-0.50 (1H, m), 0.09-0.01 (1H, m).

Intermediate 8: Methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Methyl 5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 9, 0.310 g) was suspended in methanol (7.5 mL) and concentrated sulfuric acid (4 drops) was added. The mixture was heated at reflux, under an atmosphere of nitrogen, for 36 hours. A further 2 drops of concentrated sulfuric acid was added and heating was continued for a further 24 hours. After cooling, the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous potassium carbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20%, to give methyl 5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.120 g) as an off-white solid.

¹H NMR (CDCl₃) δ: 7.06 (1H, d), 6.26 (1H, d), 4.33 (1H, d), 3.87 (3H, s), 3.85 (1H, d), 1.83 (1H, td), 1.64 (1H, m), 0.99-0.89 (2H, m).

Intermediate 8A: Methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Sample from Intermediate 8 was subjected to chiral SFC separation using a Lux C-3 column, 50 mm×250 mm, particle size 5 micron. Eluting with 5% methanol (+0.1% diethylamine) in CO₂ to give methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate as the first eluting enantiomer.

Intermediate 9: Methyl 5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Methyl 1,1-dibromo-5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 10, 1.13 g) was suspended in ethanol (30 mL). Zinc dust (1.17 g), followed by ammonium chloride (1.31 g) were added and the mixture was heated at reflux, under an atmosphere of nitrogen, for 6 hours. After cooling, the solid was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ether and cyclohexane, with a gradient of 5-12.5%, to give methyl 5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.310 g) as a colourless oil.

¹H NMR (CDCl₃) δ: 9.72 (1H, br, s), 7.98 (1H, d), 7.30 (1H, d), 4.36 (1H, dd), 3.91 (3H, s), 3.84 (1H, dd), 1.95 (1H, td), 1.73 (1H, m), 1.28 (9H, s), 1.03 (2H, m).

Intermediate 10: Methyl 1,1-dibromo-5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (Intermediate 11, 2.372 g) and benzyl triethyl ammonium chloride (0.373 g) were suspended in bromoform (6.45 mL) and 50% aqueous sodium hydroxide solution (3.64 mL) was added dropwise. The resultant black suspension was heated at 60° C. for 2 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The emulsion formed was filtered through a pad of Celite and the organic layer was decanted off. The aqueous was re-extracted with ethyl acetate and the combined organic layers were dried (MgSO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 2.5-15%, to give methyl 1,1-dibromo-5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (1.557 g) as an off-white solid.

¹H NMR (CDCl₃) δ: 9.89 (1H, br, s), 8.13 (1H, d), 7.43 (1H, d), 4.47 (1H, dd), 4.32 (1H, dd), 3.91 (3H, s), 2.89 (1H, d), 2.45 (1H, ddd), 1.30 (9H, s).

Intermediate 11: Methyl 7-(2,2-dimethylpropionoylamino)-2H-chromene-8-carboxylate

A solution of methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (Intermediate 12, 4.74 g) and [bis(trifluoromethanesulfonyl)imidate]-(triphenylphosphine)-gold (2:1) toluene adduct (0.06 g) in toluene (70 mL) was heated at 85° C., under an atmosphere of nitrogen for 3 hours. After cooling, the mixture was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20%, to give methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (3.59 g) as a colourless oil.

¹H NMR (CDCl₃) δ: 10.02 (1H, br, s), 8.05 (1H, d), 7.05 (1H, d), 6.39 (1H, ddd), 5.76 (1H, dt), 4.83 (2H, dd), 3.93 (3H, s), 1.30 (9H, s).

Intermediate 12: Methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate

A mixture of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 13, 4.57 g), propargyl bromide (80% solution in toluene, 2.03 mL) and potassium carbonate (3.74 g) in acetone (35 mL) was heated at reflux for 8 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20%, to give methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (4.74 g) as an oil which crystallised on standing to give a white solid.

¹H NMR (CDCl₃) δ: 9.89 (1H, br, s), 8.16 (1H, dd), 7.41 (1H, t), 6.83 (1H, dd), 4.74 (2H, d), 3.95 (3H, s), 2.53 (1H, t), 1.31 (9H, s).

Intermediate 13: Methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate

Trimethylacetyl chloride (3.69 g) was added to a mixture of methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al, US2004 0167128, 3.99 g) and sodium bicarbonate (2.57 g) in ethyl acetate (77 mL) and water (18 mL). The mixture was stirred at room temperature for 1 hour. A further amount of trimethylacetyl chloride (1.85 g) was added and the mixture was stirred for 1 hour. A further amount of trimethylacetyl chloride (0.920 g) was added and the mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate, the layers were separated and the organic layer was dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25%, to give methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (5.79 g) as a white solid.

¹H NMR (CDCl₃) δ: 10.32 (1H, br, s), 8.22 (1H, dd), 7.41 (1H, t), 6.71 (1H, dd), 4.08 (3H, s), 1.33 (9H, s).

Intermediate 14: Methyl (1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)-cyclopropyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A mixture of methyl (1aR,7bS)-5-{N-[4-fluoro-2-(2-methanesulfonyloxymethyl-cyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 2, 0.15 mg) and pyrrolidine (0.7 mL) in DCE (2 mL) was heated at 45° C. in a sealed vial for 3 hours. The volatiles were removed by evaporation and the residue was purified by chromatography on silica, eluting with a mixture of methanol and ethyl acetate, with a gradient of 0-20%, to give methyl (1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.077 g).

LCMS (Method A) r/t 2.37 (M+H) 501.

Intermediate 15: Methyl (1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Sodium triacetoxyborohydride (0.335 g) was added to a solution of methyl (1aR,7bS)-5-[2-(2,2-dimethyl-3-oxopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 16, 0.366 g) and diethylamine (0.173 g) in DCM (5 mL) and the mixture was stirred at room temperature for 3 days then left to stand for 4 days. The mixture was diluted with DCM and washed with water, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-12%, to give methyl (1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.138 g) as a colourless gum.

LCMS (Method D) r/t 2.66 and 2.79 (M+H) 519.

Intermediate 16: Methyl (1aR,7bS)-5-[2-(2,2-dimethyl-3-oxopropyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of methyl (1aR,7bS)-5-{2-[2-(1,3-dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 17, 0.41 g) in water (2 mL), THF (20 mL) and concentrated hydrochloric acid (2 mL) was heated at 60° C. for 90 minutes. After cooling, the volatiles were removed by evaporation and the residue was partitioned between water and DCM. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo to give methyl (1aR,7bS)-5-[2-(2,2-dimethyl-3-oxopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.371 g) as a colourless gum.

LCMS (Method D) r/t 4.14 (M+Na) 484.

Intermediate 17: Methyl (1aR,7bS)-5-{2-[2-(1,3-dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

A solution of 2-[2-(1,3-dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzenesulfonyl chloride (Intermediate 18, 0.484 g) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 8A, 0.219 g) in pyridine (2 mL) and DCM (4 mL) was left to stand at room temperature for 17 hours. The volatiles were removed by evaporation and the residue was partitioned between DCM and water. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-30%, to give methyl (1aR,7bS)-5-{2-[2-(1,3-dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate as a colourless gum (0.415 g).

LCMS (Method D) r/t 4.36 (M+Na) 528.

Intermediate 18: 2-[2-(1,3-Dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzenesulfonyl chloride

n-Butyllithium (1.6M in hexanes, 4.7 mL) was added to a solution of 2-[1-(2-bromo-5-fluorophenyl)-2-methylpropan-2-yl]-1,3-dioxolane (Intermediate 19, 2.13 g) in anhydrous THF (40 mL) at −78° C. under an atmosphere of nitrogen. The mixture was stirred for 30 minutes then sulfur dioxide was bubbled through the solution for 30 minutes. The cooling bath was removed and the mixture was allowed to warm to room temperature slowly. The volatiles were removed by evaporation and a mixture of N-chlorosuccinimide (0.94 g) in DCM (40 mL) was added to the residue. The mixture was stirred at room temperature for 30 minutes and then washed with water, dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo to give 2-[2-(1,3-dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzene-sulfonyl chloride (1.86 g) as a pale coloured oil.

¹H NMR (CDCl₃) δ: 8.15 (1H, dd), 7.14-7.06 (1H, m), 6.95-6.84 (1H, m), 4.68 (1H, s), 4.02-3.84 (4H, m), 3.26 (2H, s), 0.96 (6H, s).

Intermediate 19: 2-[1-(2-Bromo-5-fluorophenyl)-2-methylpropan-2-yl]-1,3-dioxolane

A mixture of 3-(2-bromo-5-fluorophenyl)-2,2-dimethylpropanal (Intermediate 20, 2.59 g), 4-toluenesulfonic acid (0.19 g) and ethylene glycol (3.1 g) in toluene (50 mL) was stirred and heated at reflux with a Dean-Stark apparatus for 3 hours. After cooling, the mixture was washed with a saturated solution of sodium bicarbonate and water, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-5%, to give 2-[1-(2-bromo-5-fluorophenyl)-2-methylpropan-2-yl]-1,3-dioxolane (2.65 g) as a pale coloured oil.

¹H NMR (CDCl₃) δ: 7.50 (1H, dd), 7.02 (1H, dd), 6.84-6.76 (1H, m), 4.64 (1H, s), 4.04-3.88 (4H, m), 2.88 (2H, s), 0.95 (6H, s).

Intermediate 20: 3-(2-Bromo-5-fluorophenyl)-2,2-dimethylpropanal

A solution of 2-methylpropionaldehyde (1.19 g) and 2-bromomethyl-4-fluorobromobenzene (4.02 g) in toluene (2 mL) was added to a stirred suspension of ground NaOH (0.66 g) and tetrabutyl ammonium iodide (0.111 g) in toluene (9 mL) at 60° C. under an atmosphere of nitrogen. The mixture was stirred at 60° C. for 20 hours and then left to stand at room temperature for 3 days. The mixture was partitioned between ethyl acetate and water and the organic layer was dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-5%, to give 3-(2-bromo-5-fluorophenyl)-2,2-dimethylpropanal (2.61 g) as a colourless oil.

¹H NMR (CDCl₃) δ: 9.60 (1H, s), 7.49 (1H, dd), 6.95-6.76 (2H, m), 3.01 (2H, s), 1.12 (6H, s).

Intermediate 21: Methyl (1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate

A mixture of methyl (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 22, 2.13 g) and potassium carbonate (2.76 g) in methanol (30 mL) was stirred at room temperature for 1.5 hour, then heated at 55° C. for 1 hour. After cooling, the volatiles were removed by evaporation and the residue was partitioned between water and ethyl acetate. The aqueous phase was acidified by addition of acetic acid and extracted with ethyl acetate, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-40%, to give methyl (1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (1.14 g) as a light coloured foam.

LCMS (Method D) r/t 4.48 and 4.62 (M+H) 461.

Intermediate 22: Methyl (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of 4-fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonyl chloride (Intermediate 23, 1.7 g) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 0.996 g) in pyridine (5 mL) and DCM (5 mL) was left to stand at room temperature for 4 hours. The volatiles were removed by evaporation and the residue was partitioned between DCM and 2M aqueous hydrochloric acid. The organic layer was dried through a phase separator and then concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-35%, to give methyl (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (2.17 g) as a white foam.

LCMS (Method D) r/t 4.15 and 4.21 (M+Na) 579.

Intermediate 23: 4-Fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonyl chloride

Chlorosulphonic acid (6 mL) was added to an ice-cooled solution of 2,2,2-trifluoro-1-[(R)-3-(3-fluorobenzyl)pyrrolidin-1-yl]ethanone (Intermediate 24, 2.0 g) in chloroform (10 mL). The cooling bath was removed and the mixture was stirred at room temperature 45 minutes. The mixture was poured into a mixture of ice and ethyl acetate and the organic phase was washed with a saturated solution of sodium bicarbonate, then dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to give 4-fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonyl chloride (1.72 g) as a colourless and viscous gum.

LCMS (Method D) r/t 4.16 (M+H) 374.

Intermediate 24: 2,2,2-Trifluoro-1-[(R)-3-(3-fluorobenzyl)pyrrolidin-1yl]ethanone

A solution of tert-butyl (R)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate (Intermediate 25 (2.21 g) in TFA (10 mL) and DCM (10 mL) was left to stand at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was azeotroped with toluene. The residue was dissolved in DCM (30 mL) and cooled in an ice bath. A mixture of triethylamine (2.52 g) and trifluoroacetic anhydride (2.1 g) was added and the mixture was then stirred for 30 minutes. The mixture was washed with water and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20%, to give 2,2,2-trifluoro-1-[(R)-3-(3-fluorobenzyl)pyrrolidin-1-yl]ethanone (2.02 g) as a colourless oil.

LCMS (Method D) r/t 4.04 (M+H) 276.

Intermediate 25: tert-Butyl (R)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate

Nickel Iodide (0.147 g), trans-2-aminocyclohexanol HCl salt (0.74 g), 3-fluorobenzene boronic acid (0.78 g) and sodium hexamethyldisilazide (0.208 g) were placed in a sealed tube and the mixture was degassed and purged with argon. Isopropanol (8 mL) was added and the mixture was stirred and heated at 40° C. for 5 minutes. A solution of tert-butyl (R)-3-iodomethylpyrrolidine-1-carboxylate (Intermediate 26, 1.44 g) in isopropanol (8 mL) was added and the mixture was heated at 70° C. overnight. After cooling, the mixture was diluted with ethyl acetate, filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-60%, to give tert-butyl (3R)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate (0.515 g) as an oil.

¹H NMR (CDCl₃) δ: 7.27-7.21 (2H, m), 6.95-6.84 (2H, m), 3.51-3.39 (2H, m), 3.31-3.19 (1H, m), 2.98 (1H, dd), 2.69-2.62 (2H, m), 2.47-2.30 (1H, m), 1.98-1.85 (1H, m), 1.64-1.47 (1H, m), 1.46 (9H, s).

Intermediate 26: tert-Butyl (R)-3-iodomethylpyrrolidine-1-carboxylate

Iodine (1.91 g) was added in portions to a vigorously stirred, ice cooled suspension of imidazole (0.681 g) and triphenylphosphine (1.97 g) in diethyl ether (12 mL). The reaction mixture was stirred for 10 minutes before a solution of tert butyl (R)-3-hydroxymethylpyrrolidine-1-carboxylate (1 g) in dioxane (6 mL) was added dropwise. The mixture was stirred at room temperature overnight, then diluted with diethyl ether and filtered. The solid was washed with diethyl ether and the combined filtrates were evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane, with a gradient of 0-20%, to give tert-butyl (R)-3-iodomethylpyrrolidine-1-carboxylate (1.44 g) as an oil.

¹H NMR (CDCl₃) δ: 3.64-3.46 (2H, m), 3.33 (1H, m), 3.19 (2H, d), 3.02 (1H, dd), 2.49 (1H, m), 2.07 (1H, m), 1.65 (1H, m), 1.46 (9H, s).

Intermediate 27: Methyl (1aR,7bS)-5-[4-fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 21 starting from methyl (1aR,7bS)-5-{4-fluoro-2-[(S)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 28), as an off-white foam.

LCMS (Method D) r/t 2.50 and 2.62 (M+H) 461.

Intermediate 28: Methyl (1aR,7bS)-5-{4-fluoro-2-[(S)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of 4-fluoro-2-[(S)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonyl chloride (Intermediate 29, 0.6 g) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 0.352 g) in pyridine (3 mL) and DCM (3 mL) was left to stand at room temperature for 20 hours. The volatiles were removed by evaporation and the residue was partitioned between DCM and 2M aqueous hydrochloric acid. The organic layer was dried through a phase separator and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-30%, to give methyl (1aR,7bS)-5-{4-fluoro-2-[(S)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.806 g) as a white foam.

LCMS (Method D) r/t 4.15 and 4.21 (M+Na) 579.

Intermediate 29: 4-Fluoro-2-((S)-1-trifluoroacetylpyrrolidin-3-ylmethyl)benzenesulfonyl chloride

Prepared by proceeding in a similar manner to Intermediate 23 starting from 2,2,2-trifluoro-1-[(S)-3-(3-fluorobenzyl)pyrrolidin-1-yl]ethanone (Intermediate 30), as a colourless, viscous gum.

LCMS (Method D) r/t 4.16 (M+H) 374.

Intermediate 30: 2,2,2-Trifluoro-1-[(S)-3-(3-fluorobenzyl)pyrrolidin-1-yl]ethanone

Prepared by proceeding in a similar manner to Intermediate 24 starting from tert-butyl (S)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate (Intermediate 31), as a colourless oil.

LCMS (Method D) r/t 4.04 (M+H) 276.

Intermediate 31: tert-Butyl (S)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate

Prepared by proceeding in a similar manner to Intermediate 25 starting from tert-butyl (S)-3-iodomethylpyrrolidine-1-carboxylate (Intermediate 32).

¹H NMR (CDCl₃) δ: 7.27 (1H, m), 6.97-6.83 (3H, m), 3.46 (2H, m), 3.25 (1H, m), 2.98 (1H, m), 2.67 (2H, m), 2.40 (1H, m), 1.91 (1H, m), 1.58 (1H, m), 1.45 (9H, s).

Intermediate 32: tert-Butyl (3S)-3-iodomethylpyrrolidine-1-carboxylate

Prepared by proceeding in a similar manner to Intermediate 26 starting from tert-butyl (S)-3-hydroxymethylpyrrolidine-1-carboxylate.

¹H NMR (CDCl₃) δ: 3.59 (1H, dd), 3.51 (1H, m), 3.33 (1H, m), 3.19 (2H, d), 3.02 (1H, dd), 2.49 (1H, m), 2.07 (1H, m), 1.65 (1H, m), 1.46 (9H, s).

Intermediate 33: Methyl (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)-pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A mixture of methyl (1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 21, 0.138 g) and 2,2-dimethyloxirane (0.27 mL) in methanol (3 mL) was irradiated in the microwave at 100° C. for 3 hours. After cooling, the volatiles were removed by evaporation and the residue was purified by chromatography on silica, eluting with a mixture of methanol and ethyl acetate, with a gradient of 0-20%, to give methyl (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.14 g).

LCMS (Method B) r/t 2.44 (M+H) 533.

Intermediate 34: Methyl (1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Pyridine (1 mL) was added to a mixture of 2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 35, 0.11 g) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 0.17 g) in DCM (4 mL) and the mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted with further DCM and the combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the resultant residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-20%, to give methyl (1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.053 g) as a waxy solid.

LCMS (Method B) r/t 2.44 (M+H) 501.

Intermediate 35: 2-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonyl chloride

Chlorosulphonic acid (1.7 mL) was added dropwise to a solution of 3-(3-fluorobenzyl)-1-azabicyclo[2.2.2]octane (Intermediate 36, 0.56 g) in DCE (8 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes and at 20° C. for 30 minutes. The mixture was then poured into a mixture of ice and water and extracted with DCM. The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to give 2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (180 mg) as a gum.

LCMS (Method A) r/t 0.26 (M+H) 318.

Intermediate 36: 3-(3-Fluorobenzyl)-1-azabicyclo[2.2.2]octane

A mixture of E and Z isomers of 3-(3-fluorobenzylidene)-1-azabicyclo[2.2.2]octane (Intermediate 37, 0.56 g) and palladium on carbon (0.1 g) in IMS (20 mL) was stirred at room temperature under an atmosphere of hydrogen for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give 3-(3-fluorobenzyl)-1-azabicyclo[2.2.2]octane (560 mg) as a colourless oil.

¹H NMR (CDCl₃) δ: 7.26-7.19 (1H, m), 6.95-6.83 (3H, m), 3.10-3.01 (1H, m), 2.95-2.73 (4H, m), 2.72-2.58 (2H, m), 2.47-2.39 (1H, m), 2.02-1.87 (1H, m), 1.85-1.75 (1H, m), 1.66-1.55 (2H, m), 1.53-1.37 (2H, m).

Intermediate 37: 3-(3-Fluorobenzylidene)-1-azabicyclo[2.2.2]octane (mixture of E and Z isomers)

To a suspension of sodium hydride (0.50 g) in DME (16 mL) was added a solution of diethyl 3-fluorobenzylphosphonate (Intermediate 38, 1.52 g) in DME (5 mL) at 20° C. under an atmosphere of nitrogen. The mixture was stirred for 30 minutes then 1-aza-bicyclo[2.2.2]octan-3-one (1.0 g) was added in a single portion. The mixture was stirred and heated at 60° C. for 30 minutes and then left to stand at room temperature for 16 hours. The mixture was partitioned between water and ethyl acetate and the aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10%, to give 3-(3-fluorobenzylidene)-1-azabicyclo[2.2.2]octane as a mixture of E and Z isomers (1.13 g) as a colourless oil.

LCMS (Method A) r/t 0.27 and 1.87 (M+H) 218.

Intermediate 38: Diethyl 3-fluorobenzylphosphonate

A mixture of 3-fluorobenzyl bromide (2 g) and triethyl phosphite (2.2 mL) was heated at 160° C. under an atmosphere of nitrogen for 4 hours. After cooling, the volatiles were removed in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-100%, to give diethyl 3-fluorobenzylphosphonate (2.46 g).

¹H NMR (CDCl₃) δ: 7.31-7.22 (1H, m), 7.11-6.89 (3H, m), 4.09-3.97 (4H, m), 3.13 (2H, d), 1.25 (6H, t).

Intermediate 39: Methyl (1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (mixture of E and Z isomers)

A mixture of 2-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonyl chloride (mixture of E and Z isomers, Intermediate 40, 0.26 g), methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 0.41 g) and pyridine (1 mL) in DCM (4 mL) was stirred at room temperature for 17 hours. The mixture was partitioned between DCM and a saturated aqueous solution of sodium bicarbonate and the aqueous phase was extracted with further DCM. The combined organic layers were dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10%, to give methyl (1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa-[c]chromene-4-carboxylate as a mixture of E and Z isomers (0.1 g) as a white solid.

LCMS (Method A) r/t 2.34 (M+H) 499.

Intermediate 40: 2-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonyl chloride (mixture of E and Z isomers)

Prepared by proceeding in a similar manner to Intermediate 35, starting from 3-(3-fluorobenzylidene)-1-azabicyclo[2.2.2]octane (mixture of E and Z isomers), Intermediate 37).

LCMS (Method A) r/t 2.02 and 2.07 (M+H) 316.

Intermediate 41: Methyl (1aR,7bS)-5-{2-[(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (mixture of E and Z isomers)

To a solution of tert-butyl 3-[5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)benzylidene]piperidine-1-carboxylate (mixture of E and Z isomers, Intermediate 42, 0.5 g) in DCM (8 mL) was added TFA (8 mL) and the mixture was stirred for 30 minutes. The volatiles were removed by evaporation and the residue was azeotroped with toluene. The residue was dissolved in DCM (8 mL) and cooled to 0° C. Acetaldehyde (0.1 mL) was added followed by sodium triacetoxyborohydride (0.371 g) and the reaction mixture was allowed to warm slowly to room temperature and stirred for 1 hour. The mixture was partitioned between DCM and 1M aqueous sodium hydroxide solution and the organic layer was washed with water, and brine, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10%, to give methyl (1aR,7bS)-5-{2-[(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa-[c]chromene-4-carboxylate as a mixture of E and Z isomers (0.372 g).

LCMS (Method E) r/t 2.41 and 2.51 (M+H) 501.

Intermediate 42: tert-Butyl 3-[5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)benzylidene]piperidine-1-carboxylate (mixture of E and Z isomers)

Prepared by proceeding in a similar manner to Intermediate 39, starting from tert-butyl 3-(2-chlorosulfonyl-5-fluorobenzylidene)piperidine-1-carboxylate (mixture of E and Z isomers, Intermediate 43) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 8A).

LCMS (Method E) r/t 4.38 and 4.51 (M+H) 573.

Intermediate 43: tert-Butyl 3-(2-chlorosulfonyl-5-fluorobenzylidene)piperidine-1-carboxylate (mixture of E and Z isomers)

n-Butyllithium (2.5M in hexanes, 0.226 mL) was added dropwise to a solution of tert-butyl 3-(2-bromo-5-fluorobenzylidene)piperidine-1-carboxylate (mixture of E and Z isomers, Intermediate 44, 0.2 g) in anhydrous THF (2 mL) under an atmosphere of argon at −70° C. Stirring was continued at −70° C. for 30 minutes then sulfur dioxide was bubbled through the solution for 5 minutes at −70° C. The mixture was stirred at −70° C. for 30 minutes and then slowly warmed to room temperature. The volatiles were removed by evaporation and the residue was dissolved in DCM (10 mL) and cooled to −10° C. Sulfuryl chloride (0.044 mL) was added and the mixture was allowed to warm slowly to room temperature. Stirring was continued for 30 minutes and then the mixture was purified by chromatography on silica, eluting with a mixture of TBME and cyclohexane, with a gradient of 0-30%, to give tert-butyl 3-(2-chlorosulfonyl-5-fluorobenzylidene)piperidine-1-carboxylate as a mixture of E and Z isomers (0.08 g).

LCMS (Method E) r/t 4.36 (M-tBu) 334.

Intermediate 44: tert-Butyl 3-(2-chlorosulfonyl-5-fluorobenzylidene)piperidine-1-carboxylate (mixture of E and Z isomers)

Sodium hydride (60% in mineral oil, 0.404 g) was added portionwise to a stirred solution of diethyl (2-bromo-5-fluorobenzyl)phosphonate (2.98 g) and tert-butyl 3-oxo-piperidine-1-carboxylate (1.83 g) in DME (50 mL) at room temperature and stirring was continued for 18 hours. The reaction mixture was combined with a second batch obtained in a similar manner starting from of diethyl (2-bromo-5-fluoro-benzyl)phosphonate (3.22 g) and the combined mixture was treated with water then extracted with diethyl ether. The organic layer was washed with brine, dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of TBME and cyclohexane, with a gradient of 0-20%, to give tert-butyl 3-(2-chlorosulfonyl-5-fluorobenzylidene)piperidine-1-carboxylate as a mixture of E and Z isomers (1.18 g).

LCMS (Method B) r/t 4.52 (M+H) 370.

Intermediate 45: Methyl (1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 46, 0.21 g) was added to a solution of methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 0.290 g) in DCM (10 mL) and pyridine (2 mL) and the mixture was stirred at room temperature for 4 hours. The mixture was evaporated to dryness and the residue was partitioned between DCM and water. The organic layer was dried (Na₂SO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-15%, to give methyl (1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.071 g).

¹H NMR (CDCl₃) δ: 7.95-7.88 (1H, m), 7.21-7.15 (1H, m), 7.03-6.86 (3H, m), 4.31 (1H, d), 3.81-3.73 (4H, m), 2.89-2.63 (4H, m), 2.39-2.28 (2H, m), 2.09-2.08-1.95 (1H, m), 1.94-1.44 (8H, m), 1.06-0.94 (6H, m).

Intermediate 46: 2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride

A solution of 1-ethyl-3-(3-fluorobenzyl)piperidine (Intermediate 47, 0.214 g) in DCE (1 mL) was added to chlorosulfonic acid (2 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was then added dropwise to a mixture of ice and brine and extracted with DCM. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was evaporated to dryness to give 2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (0.44 g) as a solid.

¹H NMR (CDCl₃) δ: 8.17-8.11 (1H, m), 7.43-7.37 (1H, m), 7.19-7.12 (1H, m), 3.62-3.52 (1H, m), 3.42-3.32 (1H, m), 3.16 (2H, d), 3.11-2.92 (3H, m), 2.64-2.29 (3H, m), 1.91 (2H, d), 1.43 (3H, t), 1.39-1.23 (1H, m).

Intermediate 47: 1-Ethyl-3-(3-fluorobenzyl)piperidine

A solution of lithium aluminium hydride (2M in THF, 2.8 mL) was added dropwise to a solution of 1-[3-(3-fluorobenzyl)piperidin-1-yl]ethanone (Intermediate 48, 0.66 g) in anhydrous THF (20 mL) at 0° C. under argon. The mixture was stirred for 30 minutes then allowed to warm to room temperature and stirred for 2 hours. The mixture was recooled to 0° C., water was added and the mixture was extracted with ether, washed with brine, dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness to give 1-ethyl-3-(3-fluorobenzyl)piperidine (0.535 g).

¹H NMR (CDCl₃) δ: 7.25-7.17 (1H, m), 6.95-6.80 (3H, m), 2.92-2.73 (2H, m), 2.58-2.42 (2H, m), 2.42-2.26 (2H, m), 1.96-1.76 (2H, m), 1.74-1.48 (4H, m), 1.04 (3H, t), 1.00-0.84 (1H, m).

Intermediate 48: 1-[3-(3-Fluorobenzyl)piperidin-1-yl]ethanone

A mixture of 1-[3-(3-fluorobenzylidene)piperidin-1-yl]ethanone (mixture of E and Z isomers, Intermediate 49, 0.7 g), palladium hydroxide (20% on carbon, 0.07 g) in ethyl acetate (20 mL) and IMS (1 mL) was degassed by nitrogen/vacuum purging. The reaction mixture was stirred under an atmosphere of hydrogen for 21.5 hours and then filtered. The filtrate was evaporated to dryness to give 1-[3-(3-fluorobenzyl)piperidin-1-yl]ethanone (0.66 g).

¹H NMR (CDCl₃) δ: 7.31-7.17 (1H, m), 6.97-6.80 (3H, m), 4.52-4.43 (0.5H, m), 4.41-4.31 (0.5H, m), 3.76-3.65 (0.5H, m), 3.65-3.55 (0.5H, m), 3.07-2.95 (0.5H, m), 2.82-2.62 (1.5H, m), 2.60-2.49 (1H, m), 2.45-2.33 (1H, m), 2.08 (1.5H, s), 1.95 (1.5H, s), 1.83-1.63 (3H, m), 1.50-1.32 (1H, m), 1.29-1.09 (1H, m).

Intermediate 49: 1-[3-(3-Fluorobenzylidene)piperidin-1-yl]ethanone (mixture of E and Z isomers)

Acetyl chloride (0.515 mL) was added to a mixture of 3-(3-fluorobenzylidene)piperidine (mixture of E and Z isomers, Intermediate 50, 1.5 g) and N,N-di-isopropyl-N-ethylamine (2.52 mL) in anhydrous THF (50 mL) at 0° C. under nitrogen. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with water (100 mL) and extracted with ether, washed with brine, dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 75-100%, to give 1-[3-(3-fluorobenzylidene)piperidin-1-yl]ethanone as a mixture of E and Z isomers (1.38 g). ¹H NMR (CDCl₃) δ: 7.37-7.21 (1H, m), 7.04-6.82 (3H, m), 6.48-6.26 (1H, 4s), 4.39-4.00 (2H, m), 3.72-3.48 (2H, m), 2.61-2.41 (2H, m), 2.18-2.02 (3H, 4s), 1.83-1.61 (2H, m).

Intermediate 50: 3-(3-Fluorobenzylidene)piperidine hydrochloride mixture of E and Z isomers

A solution of HCl in dioxane (4M, 30 mL) was added to a solution of tert-butyl 3-(3-fluorobenzylidene)piperidine-1-carboxylate (mixture of E and Z isomers, Intermediate 51, 2.38 g) in diethyl ether (30 mL) and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo and the residue was treated with diethyl ether. The solid was collected by filtration, washed with diethyl ether and dried in vacuo to give 3-(3-fluorobenzylidene)piperidine hydrochloride as a mixture of E and Z isomers (1.64 g).

¹H NMR (CDCl₃) 3:2 ratio of E and Z isomers δ: 9.34 (2H, br s), 7.48-7.37 (1H, m), 7.22-7.00 (3H, m), 6.59 (1H, s), 3.78-3.68 (2H, m), 3.13 (2H, m), 2.52 (1.2H, m), 2.43 (0.8H, m), 1.84 (1.2H, m), 1.76 (0.8H, m).

Intermediate 51: tert-Butyl 3-(3-fluorobenzylidene)piperidine-1-carboxylate (mixture of E and Z isomers)

(3-Fluorobenzyl)(triphenyl)phosphonium bromide (Intermediate 52, 5.3 g) was added in portions to a solution of sodium tert-butoxide (1.06 g) in anhydrous THF (20 mL) at room temperature and the resultant mixture was stirred for 30 minutes. A solution of tert-butyl 3-oxopiperidine-1-carboxylate (2 g) in anhydrous THF (10 mL) was added dropwise at room temperature and the mixture was stirred for 24 hours. The mixture was diluted with water and extracted with ether, washed with brine, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20%, to give tert-butyl 3-(3-fluorobenzylidene)piperidine-1-carboxylate as a 3:2 mixture of E and Z isomers (1.42 g).

¹H NMR (CDCl₃) δ: 7.33-7.21 (1H, m), 7.05-6.85 (3H, m), 6.37 (0.6H, s), 6.28 (0.4H, s), 4.16 (0.8H, s), 4.00 (1.2H, s), 3.50 (2H, t), 2.50 (1.2H, m), 2.39 (0.8H, m), 1.72 (0.8H, m), 1.62 (1.2H, m), 1.48 (5.4H, s), 1.34 (3.6H, br s).

Intermediate 52: (3-Fluorobenzyl)(triphenyl)phosphonium bromide

A mixture of 3-fluorobenzyl bromide (5 g) and triphenyl phosphine (6.94 g) in toluene (50 mL) was heated at reflux for 3 hours. After cooling, the solid was collected by filtration, washed with toluene and dried under vacuum at 50° C. to give (3-fluorobenzyl)(triphenyl)phosphonium bromide (10.1 g).

¹H NMR (DMSO-d₆) δ: 7.96-7.87 (3H, m), 7.81-7.64 (12H, m), 7.35-7.26 (1H, m), 7.20-7.11 (1H, m), 6.88-6.82 (1H, m), 6.78-6.70 (1H, m), 5.21 (2H, d).

Intermediate 53: Methyl (1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 88, starting from 2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonyl chloride (Intermediate 54) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A) as a glass.

LCMS (Method A) r/t 2.34 and 2.42 (M+H) 503.

Intermediate 54: 2-[2-((S)-1-Ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonyl chloride

Prepared by proceeding in a similar manner to Intermediate 35, starting from (S)-1-ethyl-2-[2-(3-fluorophenyl)ethyl]pyrrolidine (Intermediate 55), as an oil.

¹H NMR (CDCl₃) δ: 8.10 (1H, dd), 7.42 (1H, d), 7.13 (1H, t), 3.97-3.84 (1H, m), 3.47-3.19 (3H, m), 3.17-2.80 (3H, m), 2.48-2.21 (3H, m), 2.16-1.96 (3H, m), 1.54-1.41 (3H, m).

Intermediate 55: (S)-1-Ethyl-2-[2-(3-fluorophenyl)ethyl]pyrrolidine

Lithium aluminium hydride (2M in THF, 1.42 mL) was added to a solution of 1-{(S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidin-1-yl}ethanone (Intermediate 56, 0.19 g) in THF (7 mL) at room temperature under an atmosphere of nitrogen. The mixture was heated at 60° C. for 2 hours then allowed to cool to room temperature and carefully treated with water (0.15 mL) followed by 4M sodium hydroxide solution (0.15 mL) and then water (0.36 mL) at 0° C. Anhydrous sodium sulfate was added and the suspension was diluted with ether and filtered through Celite. The filtrate was concentrated in vacuo to give (S)-1-ethyl-2-[2-(3-fluorophenyl)ethyl]pyrrolidine (0.15 g) as an oil.

LCMS (Method A) r/t 1.73 (M+H) 222.

Intermediate 56: 1-{(S)-2-[2-(3-Fluorophenyl)ethyl]pyrrolidin-1-yl}ethanone

A mixture of (S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidine (Intermediate 57, 0.167 g) and acetyl chloride (0.123 mL) in DCM (5 mL) was stirred at room temperature for 1.5 hours. The resultant solution was washed with 1M hydrochloric acid, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to give 1-{(S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidin-1-yl}ethanone (0.19 g) as an oil.

¹H NMR (CDCl₃) δ: 7.29-7.17 (1H, m), 7.01-6.81 (3H, m), 3.49-3.35 (2H, m), 2.75-2.50 (2H, m), 2.23-2.12 (1H, m), 2.06-1.83 (7H, m), 1.82-1.68 (1H, m), 1.64-1.49 (1H, m).

Intermediate 57: (S)-2-[2-(3-Fluorophenyl)ethyl]pyrrolidine

A solution of tert-butyl (S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidine-1-carboxylate (Intermediate 58, 0.307 g) in DCM (5 mL) was treated with TFA (5 mL) and the mixture was stirred at room temperature for 1 hour. The volatiles were removed by evaporation and the residue was dissolved in acetonitrile and purified by SCX cartridge. The cartridge was washed with acetonitrile followed by methanol and the product was eluted with 2M ammonia in methanol to give (S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidine (0.167 g) as an oil.

¹H NMR (CDCl₃) δ: 7.27-7.19 (1H, m), 6.98 (1H, d), 6.95-6.83 (2H, m), 3.07-2.95 (2H, m), 2.90-2.82 (1H, m), 2.79-2.57 (2H, m), 1.97-1.65 (6H, m), 1.39-1.25 (1H, m).

Intermediate 58: tert-Butyl (S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidine-1-carboxylate

A solution of tert-butyl (R)-2-[(E)-2-(2-bromo-5-fluorophenyl)ethenyl]pyrrolidine-1-carboxylate (Intermediate 59, 0.37 g) in ethanol (20 mL) was treated with 10% palladium on carbon (0.1 g) and the mixture was stirred at room temperature under an atmosphere of hydrogen for 36 hours. The mixture was diluted with isopropanol and filtered through Celite and the filtrate was evaporated to dryness to give tert-butyl (S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidine-1-carboxylate (0.307 g).

LCMS (Method A) r/t 4.26 (M-tBu) 238.

Intermediate 59: tert-Butyl (R)-2-[(E)-2-(2-bromo-5-fluorophenyl)ethenyl]pyrrolidine-1-carboxylate

A solution of diethyl (2-bromo-5-fluorobenzyl)phosphonate (0.325 g) and tert-butyl (R)-2-formylpyrrolidine-1-carboxylate (0.2 g) in anhydrous THF (5 mL) was treated with sodium hydride (60% dispersion in mineral oil, 0.048 g). The mixture was stirred at room temperature for 2 hours, then diluted with water and extracted with ether. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo to give tert-butyl (R)-2-[(E)-2-(2-bromo-5-fluorophenyl)ethenyl]pyrrolidine-1-carboxylate (0.37 g) as an oil.

¹H NMR (CDCl₃) δ: 7.56-7.45 (1H, m), 7.23-1.16 (1H, m), 6.89-6.78 (1H, m), 6.71 (1H, d), 6.08 (1H, br s), 3.80-3.73 (1H, m), 3.54-3.43 (2H, m), 2.00-1.73 (4H, m), 1.46 (9H, br s).

Intermediate 60: Methyl (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Tetra-n-butylammonium fluoride (1.0M in THF, 0.65 mL) was added to a solution of methyl (1aR,7bS)-5-{(2-[(R)-1-(2-tert-butyldimethylsilyloxyethyl)pyrrolidin-3-ylmethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 61, 0.14 g) in THF (5 mL) at room temperature under an atmosphere of nitrogen and stirring was continued for 19 hours. The mixture was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and ethyl acetate, with a gradient of 0-20%, to give methyl (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.034 g).

LCMS (Method B) r/t 2.33 (M+H) 505.

Intermediate 61: Methyl (1aR,7bS)-5-{(2-[(R)-1-(2-tert-butyldimethylsilyloxyethyl)-pyrrolidin-3-ylmethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Sodium triacetoxyborohydride (0.127 g) was added to a solution of methyl (1aR,7bS)-5-[(2-((R)-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 21, 0.138 g) and (tert-butyldimethylsilyloxy)acetaldehyde (0.105 g) in DCM (3 mL) and stirring was continued at room temperature for 22 hours. The mixture was diluted with DCM and the organic layer was washed with water and brine, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-10% followed by a mixture of ethyl acetate and cyclohexane, with a gradient of 30-100% and finally by a mixture of methanol and ethyl acetate, with a gradient of 0-20%, to give methyl (1aR,7bS)-5-{(2-[(R)-1-(2-tert-butyldimethylsilyloxyethyl)-pyrrolidin-3-ylmethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.138 g) as a pale yellow foam. LCMS (Method D) r/t 3.37 (M+H) 619.

Intermediate 62: Methyl (1aR,7bS)-5-[2-(8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 34, starting from, 2-(8-ethyl-8-azabicyclo[3.2.1]oct-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 63) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A).

LCMS (Method A) r/t 2.87 and 2.91 (M+H) 529.

Intermediate 63: 2-(8-Ethyl-8-azabicyclo[3.2.1]oct-3-ylmethyl)-4-fluorobenzenesulfonyl chloride

Chlorosulphonic acid (0.43 mL) was added dropwise to a solution of 8-ethyl-3-(3-fluorobenzyl)-8-azabicyclo[3.2.1]octane (Intermediate 64, 0.161 g) in DCE (2 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes and then poured into a mixture of ice and water. The aqueous phase was extracted with DCM and the combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to give 2-(8-ethyl-8-azabicyclo[3.2.1]oct-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (0.115 g) as a foam. LCMS (Method A) r/t 2.55 and 2.73 (M+H) 346.

Intermediate 64: 8-Ethyl-3-(3-fluorobenzyl)-8-azabicyclo[3.2.1]octane

Ethyl iodide (0.11 mL) was added to a mixture of 3-(3-fluorobenzyl)-8-azabicyclo[3.2.1]octane (Intermediate 65, 0.31 g) and potassium carbonate (0.19 g) in DMF (3 mL) and stirring was continued at room temperature for 3 days. The volatiles were removed by evaporation and the residue was purified by SCX cartridge. The cartridge was washed with methanol and the product was eluted with 2M ammonia in methanol. The residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10%, to give 8-ethyl-3-(3-fluorobenzyl)-8-azabicyclo[3.2.1]octane (0.166 g) as a brown oil.

LCMS (Method A) r/t 2.49 (M+H) 248.

Intermediate 65: 3-(3-Fluorobenzyl)-8-azabicyclo[3.2.1]octane

A mixture of benzyl 3-(3-fluorobenzylidene)-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate 66, 0.522 g) and 10% palladium on carbon (0.1 g) in ethanol (40 mL) was stirred under an atmosphere of hydrogen for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The resultant oil was dissolved in ethanol (40 mL), treated with 10% palladium on carbon (0.1 g) and stirred under an atmosphere of hydrogen for 48 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give 3-(3-fluorobenzyl)-8-azabicyclo[3.2.1]octane (0.315 g) as a colourless oil.

LCMS (Method B) r/t 0.26, 0.37 and 2.05 (M+H) 220.

Intermediate 66: Benzyl 3-(3-fluorobenzylidene)-8-azabicyclo[3.2.1]octane-8-carboxylate

Diethyl 3-fluorobenzylphosphonate (Intermediate 38, 1.5 g) in DME (10 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 0.24 g) in DME (15 mL) at room temperature and the resultant mixture was stirred under an atmosphere of nitrogen at room temperature for 30 minutes. Benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.58 g) in DME (10 mL) was then added and stirring was continued for 16 hours. The mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted with further ethyl acetate. The combined organic layers were dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-60%, to give benzyl 3-(3-fluorobenzylidene)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.5 g) as a colourless oil which solidified on standing.

LCMS (Method A) r/t 4.40 (M+H) 352.

Intermediate 67: Methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methyl-pyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Methane sulfonic anhydride (0.159 g) was added to a stirred, cooled mixture of methyl (1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 68, 0.3 g) and N,N-diisopropyl-N-ethylamine (0.237 g) in DCM (30 mL) at 0° C. The resulting solution was stirred for 15 minutes at 0-5° C. then 3-methylpyrrolidin-3-ol (0.124 g) was added and stirring was continued at room temperature for 18 hours. The mixture was quenched by addition of water and the mixture was extracted with DCM. The organic phase was dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo to give methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]-benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.34 g) as a yellow solid.

The compound was used without further characterization.

Intermediate 68: Methyl (1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzene-sulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

A mixture of methyl (1aR,7bS)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 69, 5.0 g), (Z)-3-(tributylstannanyl)prop-2-en-1-ol (Intermediate 70, 5.06 g), tris-(dibenzylideneacetone)dipalladium (0.89 g) and tri-tert-butylphosphonium tetrafluoroborate (0.56 g) in dioxane (50 mL) and DMSO (5 mL) was stirred at room temperature for 1 hour. The mixture was quenched by the addition of 5 mL of saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate, washed with water, dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether, with a gradient of 30-50%, to give methyl (1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (4.5 g) as an off-white solid.

¹H NMR (CDCl₃) δ: 8.19 (1H, m), 7.39 (1H, d), 7.16 (1H, m), 7.02 (1H, m), 6.96 (2H, m), 6.03 (1H, m), 4.41 (1H, m), 4.23 (2H, m), 3.88 (1H, dd), 3.71 (3H, 2s), 3.65 (3H, 2s), 2.06 (1H, m), 1.82 (1H, m), 1.25 (1H, m), 1.14 (1H, m).

Intermediate 69: Methyl (1aR,7bS)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

To a solution of methyl (1aR,7bS)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 6, 6.0 g) in THF (60 mL) under an atmosphere of nitrogen was added sodium hydride (60% oil dispersion, 1.05 g) in several batches. The resulting solution was stirred at room temperature for 30 minutes then methyl chloroformate (2.49 g) was added dropwise and the solution was stirred at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added and the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo. The residue was triturated with hexane and the solid was collected by filtration to give methyl (1aR,7bS)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (6.4 g) as a yellow solid.

¹H NMR (CDCl₃) δ: 8.42 (1H, m), 7.48 (1H, dd), 7.37 (1H, d), 7.19 (2H, m), 4.42 (1H, m), 3.95 (1H, dd), 3.86 (3H, s,), 3.69 (3H, s), 2.06 (1H, m), 1.84 (1H, m), 1.16 (2H, m).

Intermediate 70: (Z)-3-(tributylstannanyl)prop-2-en-1-ol

Propargyl alcohol (5 mL) was added to a solution of lithium aluminium hydride (1M in THF, 43 mL) in THF (70 mL) at −78° C. The resultant mixture was warmed to room temperature, stirred for 18 hours and then re-cooled to −78° C. A solution of tri-n-butyl tin chloride (8.32 mL) in diethyl ether (50 mL) was added and stirring was continued for 3 hours while the mixture gradually warmed to room temperature. The mixture was cooled to −5° C. and quenched by addition of water and 15% aqueous sodium hydroxide solution then it was warmed to room temperature. Ethyl acetate was added and the mixture was stirred for 1 hour then filtered through Celite. The filtrate was evaporated to dryness and the residue was purified by chromatography on a silica column which had been pre-washed with 20% triethylamine in acetonitrile. The column was eluted with a mixture of ethyl acetate and pentane, with a gradient of 0-10%, to give (Z)-3-(tributylstannanyl)prop-2-en-1-ol (5.06 g) as a clear oil.

¹H NMR (CDCl₃) δ: 6.70 (1H, dt), 6.08 (1H, dt), 4.12 (2H, dd), 1.49 (6H, m), 1.31 (6H, m), 0.98-0.84 (15H, m).

Intermediate 71: Methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enylbenzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 67, starting from methyl (1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 68) and piperidin-4-ol, as a yellow solid.

The compound was used without further characterization.

Intermediate 72: Methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enylbenzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 67, starting from methyl (1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 68) and 4-methylpiperidin-4-ol, as a yellow solid.

The compound was used without further characterization.

Intermediate 73: Methyl (1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of 3-ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 74, 0.299 g) in DCE (3 mL) was added dropwise to a mixture of chlorosulphonic acid (0.871 mL) in DCE (3 mL) at −10° C. Stirring was continued at −10° C. for 1 hour, then the mixture was allowed to warm to room temperature slowly and then stirred for 1 hour. The mixture was diluted with DCM and added carefully to a mixture of ice, water and sodium bicarbonate (3.3 g). The mixture was extracted with DCM followed by TBME. The combined organic layers were dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (3 mL) and added to a solution of methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 0.266 g) in pyridine (2 mL) and DCM (6 mL) and the mixture was stirred at room temperature for 20 hours. The volatiles were removed by evaporation and the residue was purified by chromatography on silica, eluting with a mixture of methanol and ethyl acetate, with a gradient of 0-20%, to give methyl (1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.187 g) as a yellow solid.

LCMS (Method E) r/t 2.31 (M+H) 487.

Intermediate 74: 3-Ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexane

Lithium aluminium hydride (2M in THF, 5 mL) was added dropwise to a solution of 3-ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Intermediate 75, 0.659 g) in anhydrous THF (20 mL) at 0° C. under an atmosphere of nitrogen. The mixture was allowed to warm to room temperature and then heated at reflux for 4 hours. After cooling in an ice bath, the mixture was treated with water and then extracted with diethyl ether, washed with brine, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to give 3-ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (0.529 g) as an oil.

LCMS (Method E) r/t 1.45 (M+H) 206.

Intermediate 75: 3-Ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one

A mixture of ethyl 2-chloromethyl-3-(3-fluorophenyl)cyclopropanecarboxylate, (Intermediate 76, 1 g) and ethylamine (70% in water, 5 mL) in IMS (5 mL) was heated in a sealed vial at 95° C. for 18 hours. After cooling, the volatiles were removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-100%, to give 3-ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (0.659 g) as a white solid.

LCMS (Method E) r/t 2.97 (M+H) 220.

Intermediate 76: Ethyl 2-chloromethyl-3-(3-fluorophenyl)cyclopropanecarboxylate

A solution of ethyl diazoacetate (9.66 g) in DCM (20 mL) was added dropwise over 7 hours via syringe pump to a mixture of 1-((E)-3-chloroprop-1-enyl)-3-fluorobenzene (Intermediate 77, 5.16 g) and rhodium acetate dimer (0.2 g) in DCM (30 mL) at room temperature under an atmosphere of argon and stirring was continued for 72 hours. The volatiles were removed by evaporation and the residue was purified by chromatography on silica, eluting with a mixture of DCM and cyclohexane, with a gradient of 0-25%, to give ethyl 2-chloromethyl-3-(3-fluorophenyl)cyclopropanecarboxylate (4.27 g).

¹H NMR (CDCl₃) δ: 7.30-7.18 (1H, m), 6.97-6.75 (3H, m), 4.30-4.08 (2H, m), 4.01 (1H, dd), 3.85 (1H, dd), 2.67 (1H, t), 2.26-2.00 (2H, m), 1.30 (3H, t).

Intermediate 77: 1-((E)-3-Chloroprop-1-enyl)-3-fluorobenzene

Thionyl chloride (3 mL) was slowly added to a solution of (E)-3-(3-fluorophenyl)prop-2-en-1-ol (6.23 g) in diethyl ether (100 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 hours. Additional thionyl chloride (1.5 mL) was added and stirring was continued for 2 hours. Further thionyl chloride (3 mL) was added and stirring was continued for 2.5 hours. Pyridine (two drops) was added and stirring was continued for 18 hours. The mixture was carefully quenched by addition of a saturated aqueous solution of sodium bicarbonate and water. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-35%, to give 1-((E)-3-chloroprop-1-enyl)-3-fluorobenzene (7.49 g).

¹H NMR (CDCl₃) δ: 7.32-7.24 (1H, m), 7.16-7.04 (2H, m), 7.00-6.90 (1H, m), 6.61 (1H, d), 6.31 (1H, dt), 4.22 (2H, dd).

Intermediate 78: Methyl (1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of tert-butyl (S)-2-((Z)-2-{5-fluoro-2-[(1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl]phenyl}ethenyl)pyrrolidine-1-carboxylate (Intermediate 79, 0.436 g) in DCM (10 mL) was treated with TFA (8 mL) and the mixture was stirred at room temperature for 1.5 hours. The volatiles were removed by evaporation azeotroping with toluene. The residue was partitioned between a saturated aqueous solution of sodium bicarbonate and DCM. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo to give methyl (1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.424 g) as a glass.

¹H NMR (CDCl₃) δ: 8.06-8.00 (1H, m), 7.14 (1H, d), 7.00-7.00 (2H, m), 6.87-6.79 (2H, m), 5.87-5.80 (1H, m), 4.34 (1H, d), 3.86-3.75 (4H, m), 3.10-3.01 (1H, m), 2.84-2.74 (1H, m), 1.93-1.42 (7H, m), 1.05-0.97 (2H, m).

Intermediate 79: tert-Butyl ((S)-2-((Z)-2-{5-fluoro-2-[(1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl]phenyl}ethenyl)pyrrolidine-1-carboxylate

A mixture of methyl (1aR,7bS)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 6, 0.3 g), tert-butyl (S)-2-((Z)-2-tributylstannanylethenyl)pyrrolidine-1-carboxylate (Intermediate 80, 0.85 g), tris-(dibenzylideneacetone)dipalladium (0.026 g) and tri-tert-butylphosphonium tetrafluoroborate (0.016 g) in dioxane (5 mL) and DMSO (0.5 mL) was degassed with a stream of argon and then heated in a sealed vial at 85° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate, filtered through Celite, washed with water, dried (MgSO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-10%, to give tert-butyl ((S)-2-((Z)-2-{5-fluoro-2-[(1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl]phenyl}ethenyl)pyrrolidine-1-carboxylate (0.435 g) as a glass.

LCMS (Method F) r/t 3.89 (M+H) 573.

Intermediate 80: tert-Butyl (S)-2-((Z)-2-tributylstannanylethenyl)pyrrolidine-1-carboxylate

Bis-(cyclopentadienyl)zirconium(IV) chloride hydride (0.644 g) was suspended in anhydrous THF (5 mL) and the mixture was degassed with a stream of argon and then treated with tert-butyl (S)-2-(tributylstannanylethynyl)pyrrolidine-1-carboxylate (Intermediate 81, 1.0 g). The mixture was stirred at room temperature for 2.25 hours, then additional bis-(cyclopentadienyl)zirconium(IV) chloride hydride (0.38 g) was added. Stirring was continued for a further 1.5 hours then additional bis-(cyclopentadienyl)zirconium(IV) chloride hydride (0.5 g) was added. After 1.5 hours stirring, the reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate and extracted with diethyl ether. The organic phase was dried (MgSO₄) and filtered. The filtrate was concentrated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of TBME and pentane, with a gradient of 0-20%, to give tert-butyl (S)-2-((Z)-2-tributylstannanylethenyl)pyrrolidine-1-carboxylate (1.157 g) as an oil.

¹H NMR (CDCl₃) δ: 6.44 (1H, dd), 5.85 (1H, br s), 3.96 (1H, br s), 3.55-3.35 (2H, m), 2.12-1.97 (1H, m), 1.92-1.62 (3H, m), 1.55-1.45 (6H, m), 1.42 (9H, s), 1.38-1.25 (6H, m), 1.01-0.86 (15H, m).

Intermediate 81: tert-Butyl (S)-2-(tributylstannanylethynyl)pyrrolidine-1-carboxylate

A solution of tert-butyl (S)-2-ethynylpyrrolidine-1-carboxylate (3.25 g) in anhydrous THF (125 mL) was cooled to −78° C. under a nitrogen atmosphere and treated with n-butyllithium (2.5M in hexanes, 8 mL), whilst maintaining the internal temperature below −60° C. Stirring was continued at −60° C. for 10 minutes then the mixture was allowed to warm to 0° C. and stirred at that temperature for 2.5 hours. Tributyltin chloride (5.54 mL) was added and the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The mixture was cooled to 0° C. and a saturated aqueous solution of sodium bicarbonate was added, followed by water. The mixture was extracted with ethyl acetate, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of TBME and pentane, with a gradient of 0-30%, to give tert-butyl (S)-2-(tributylstannanylethynyl)pyrrolidine-1-carboxylate (4.09 g) as a colourless oil.

1H NMR (CDCl3) δ: 4.43 (1H, br s), 3.47 (1H, br s), 3.31 (1H, br s), 2.16-1.94 (3H, m), 1.87 (1H, br s), 1.60-1.50 (6H, m), 1.49 (9H, s), 1.40-1.29 (6H, m), 0.99-0.87 (15H, m).

Intermediate 82: Methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-((S)-3-hydroxymethyl-pyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A mixture of methyl (1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 83, 0.3 g), N,N-diisopropyl-N-ethylamine (0.204 g) and (S)-pyrrolidin-3-ylmethanol (Intermediate 84, 0.107 g) in DCM (30 mL) was stirred at room temperature for 4 hours. Water was added and the mixture was extracted with DCM. The combined organic layers were dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo to give methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-((S)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.38 g) as a yellow solid.

The compound was used without further characterization.

Intermediate 83: Methyl (1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Methane sulfonic anhydride (0.87 g) was added in several batches to a stirred, cooled mixture of methyl (1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 68, 1.63 g) and N,N-diisopropyl-N-ethylamine (1.29 g) in DCM (40 mL) at 0° C. under an atmosphere of nitrogen. The resulting solution was stirred at 0-5° C. for 1 hour then a saturated aqueous solution of sodium bicarbonate was added. The mixture was extracted with DCM and the organic phase was dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether, with a gradient of 25-33%, to give methyl (1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (1.8 g) of as an off-white solid.

The compound was used without further characterization.

Intermediate 84: (S)-Pyrrolidin-3-ylmethanol

Acetyl chloride (9 mL) was added dropwise at 0° C. to methanol (40 mL) under an atmosphere of nitrogen. The mixture was stirred for 0.5 hours at 0° C. then tert-butyl (S)-3-hydroxymethylpyrrolidine-1-carboxylate (2.5 g) was added. The resulting solution was stirred at room temperature overnight then concentrated in vacuo. The residue was dissolved in isopropanol (40 mL) and potassium carbonate (10 g) was added. The mixture was stirred at room temperature overnight then filtered. The filtrate was concentrated in vacuo to give (S)-pyrrolidin-3-ylmethanol (1.24 g) as a yellow oil.

The compound was used without further characterization.

Intermediate 85: Methyl (1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-((R)-3-hydroxymethyl-pyrrolidin-1-yl)prop-1-enylbenzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 82, starting from methyl (1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 83) and (R)-pyrrolidin-3-ylmethanol, as a yellow solid.

The compound was used without further characterization.

Intermediate 86: Methyl (1aR,7bS)-5-[N-(4-fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl]benzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 82, starting from methyl (1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 83) and 2-((S)-pyrrolidin-3-yl)propan-2-ol, as a yellow solid.

The compound was used without further characterization.

Intermediate 87: Methyl (1aR,7bS)-5-[N-(4-fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl]benzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 82, starting from methyl (1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 83) and 2-((R)-pyrrolidin-3-yl)propan-2-ol, as a yellow solid.

The compound was used without further characterization.

Intermediate 88: Methyl (1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

4-Fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonyl chloride (Intermediate 89, 0.53 g) in DCM (10 mL) was added to a solution of methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 0.243 g) in DCM (15 mL) and pyridine (2 mL) and the mixture was stirred at room temperature for 21 hours. The volatiles were removed by evaporation and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-20%, to give methyl (1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.097 g) as a brown solid.

¹H NMR (CDCl₃) δ: 7.91 (1H, dd), 7.23 (1H, d), 7.07-6.99 (1H, m), 6.99-6.93 (2H, m), 4.39-4.29 (2H, m), 3.83-3.72 (4H, m), 3.57-3.46 (2H, m), 3.13-3.00 (2H, m), 3.00-2.75 (2H, m), 2.61 (1H, td), 2.35-2.22 (1H, m), 2.22-2.074 (3H, m), 1.98-1.88 (1H, m), 1.87-1.67 (2H, m), 1.59-1.43 (1H, m), 1.09-0.96 (2H, m).

Intermediate 89: 4-Fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonyl chloride

2-(3-Fluorobenzyl)hexahydro-1H-pyrrolizine (Intermediate 90, 0.365 g) in DCE (3 mL) was added dropwise to a solution of chlorosulfonic acid (1 mL) in DCE (3 mL) at −10° C. The mixture was stirred for 1 hour at −10° C. then allowed to warm to room temperature and stirred for 16 hours. The mixture was carefully added to ice and water containing sodium bicarbonate (3.78 g) and then extracted with DCM. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was evaporated to dryness.

The compound was used without further characterization.

Intermediate 90: 2-(3-Fluorobenzyl)hexahydro-1H-pyrrolizine

A mixture of 2-(3-fluorobenzylidene)hexahydro-1H-pyrrolizine (mixture of E and Z isomers, Intermediate 91, 0.4 g), palladium hydroxide (20% on carbon, 0.1 g), ethyl acetate (10 mL) and IMS (10 mL) was degassed by nitrogen/vacuum purging. The reaction mixture was stirred vigorously under an atmosphere of hydrogen for 2 hours. The mixture was filtered and the filtrate was evaporated to dryness to give 2-(3-fluorobenzyl)hexahydro-1H-pyrrolizine (0.365 g) as a brown oil.

¹H NMR (CDCl₃) δ: 7.29-7.18 (1H, m), 6.99-6.80 (3H, m), 3.89-3.77 (1H, m), 3.48-3.40 (1H, m), 3.23-3.12 (1H, m), 2.76-2.57 (4H, m), 2.30-2.10 (2H, m), 2.04-1.85 (3H, m), 1.65-1.53 (1H, m), 1.23-1.09 (1H, m).

Intermediate 91: 2-(3-Fluorobenzylidene)hexahydro-1H-pyrrolizine (mixture of E and Z isomers)

Potassium tert-butoxide (1.31 g) was added to a solution of (3-fluorobenzyl)triphenylphosphonium bromide (Intermediate 52, 4.96 g) in dry THF (50 mL) at room temperature. The mixture was stirred for 20 minutes, then a solution of tetrahydro-1H-pyrrolizin-2(3H)-one (Intermediate 92, 1.25 g) in dry THF (20 mL) was added. The mixture was stirred for 20 hours then diluted with water and extracted with ethyl acetate. The organic layer was dried (Na₂SO₄), filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10%, to give 2-(3-fluorobenzylidene)hexahydro-1H-pyrrolizine as a mixture of E and Z isomers (0.4 g).

¹H NMR (CDCl₃) δ: 7.37-7.27 (1H, m), 7.07-6.80 (3H, m), 6.52-6.42 (1H, m), 4.29-3.89 (2H, m), 3.68-3.54 (1H, m), 3.52-3.40 (1H, m), 3.12-2.97 (1H, m), 2.80-2.68 (1H, m), 2.61-2.48 (1H, m), 2.32-2.13 (1H, m), 2.08-1.93 (2H, m), 1.75-1.60 (1H, m).

Intermediate 92: Tetrahydro-1H-pyrrolizin-2(3H)-one

Ethyl (1-ethoxycarbonylmethylpyrrolidin-2-yl)acetate (Intermediate 93, 5 g) in xylene (30 mL) was added dropwise over 60 minutes to a suspension of sodium hydride (60% oil dispersion, 0.863 g) in xylene (75 mL) and IMS (0.1 mL) at 60° C. The mixture was stirred and heated at 60° C. for 1 hour, then, the temperature was raised to 75° C. and stirring was continued for 1.5 hours. After cooling, acetic acid (4.5 mL), water (15 ml) and 2M hydrochloric acid (120 mL) were added. The aqueous layer was separated and heated at 110° C. for 2 hours. After cooling, the mixture was concentrated in vacuo and the residue was dissolved in water, neutralized by addition of solid sodium carbonate and extracted with chloroform. The organic phase was dried (Na₂SO₄), filtered and the solvent was removed in vacuo to give tetrahydro-1H-pyrrolizin-2(3H)-one (1.25 g).

LCMS (Method E) r/t 0.36 (M+H) 126.

Intermediate 93: Ethyl (1-ethoxycarbonylmethylpyrrolidin-2-yl)acetate

Ethyl bromoacetate (6.05 g) was added to a mixture of ethyl pyrrolidin-2-ylacetate hydrochloride (Intermediate 94, 6.38 g) and potassium carbonate (12.3 g) in IMS (150 mL) and the mixture was heated at reflux for 4 hours. After cooling, the mixture was concentrated in vacuo and the residue was partitioned between water and diethyl ether. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was evaporated to dryness to give ethyl (1-ethoxycarbonylmethylpyrrolidin-2-yl)acetate (5.0 g).

¹H NMR (CDCl₃) δ: 4.24-4.05 (4H, m), 3.53 (1H, d), 3.31-3.14 (2H, m), 3.12-2.98 (1H, m), 2.64-2.44 (2H, m), 2.37-2.23 (1H, m), 2.15-1.98 (1H, m), 1.89-1.70 (2H, m), 1.66-1.52 (1H, m), 1.32-1.19 (6H, m).

Intermediate 94: Ethyl pyrrolidin-2-ylacetate hydrochloride

TFA (30 mL) was added slowly to a solution of ethyl 6-(tert-butoxycarbonylamino)hex-2-enoate (Intermediate 95, 10.25 g) in DCM (100 mL) at 0° C. The solution was allowed to warm to room temperature and stirred for 24 hours. The mixture was concentrated in vacuo and the residue was azeotroped with toluene and DCM. The residue was dissolved in DCM (100 mL) and cooled to 0° C. Triethylamine (27 mL) was added and the mixture was allowed to warm to room temperature and stirred for 18 hours. The volatiles were removed in vacuo and the residue was dissolved in diethyl ether (200 mL) and treated with 4M HCl in dioxane (40 mL). The mixture was stirred for 30 minutes then evaporated to dryness to give ethyl pyrrolidin-2-ylacetate hydrochloride (6.38 g).

¹H NMR (CDCl₃) δ: 9.72 (2H, br d), 4.18 (2H, q), 4.01-3.83 (1H, m), 3.48-3.34 (2H, m), 3.26-3.14 (1H, m), 2.92-2.78 (1H, m), 2.38-2.20 (1H, m), 2.18-1.95 (2H, m), 1.85-1.67 (1H, m), 1.27 (3H, t).

Intermediate 95: Ethyl 6-(tert-butoxycarbonylamino)hex-2-enoate

DIBAL (1M in toluene, 56 mL) was added dropwise to a solution of tert-butyl 2-oxo-pyrrolidine-1-carboxylate (9.8 g) in dry THF (150 mL) at −70° C. under an atmosphere of nitrogen. The mixture was stirred for 1.5 hours at −70° C., then a saturated solution of Rochelle's salt was added followed by ethyl acetate. The mixture was stirred until two clear layers formed, then the organic layer was dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was dissolved in dry toluene (200 mL) and treated with (carbethoxymethylene)triphenylphosphorane (19.54 g). The resultant mixture was heated at reflux under an atmosphere of nitrogen for 18 hours. After cooling, the mixture was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-35%, to give ethyl 6-(tert-butoxycarbonylamino)hex-2-enoate (10.25 g) as a yellow oil.

¹H NMR (CDCl₃) δ: 6.94 (1H, dt), 5.83 (1H, dt), 4.53 (1H, br s), 4.18 (2H, q), 3.20-3.07 (2H, m), 2.29-2.18 (2H, m), 1.72-1.61 (2H, m), 1.44 (9H, s), 1.28 (3H, t).

Intermediate 96: Methyl (1aR,7bS)-5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Triethylamine (2.4 mL) was added to a mixture of 5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)phenylacetic acid (Intermediate 97, 0.740 g), (R)-1-ethylpyrrolidin-3-ylamine dihydrochloride salt (Intermediate 100, 0.48 g) and EDAC (0.65 g) in DCM (20 mL) at room temperature under an atmosphere of nitrogen. The mixture was stirred at room temperature for 16 hours then diluted with DCM and washed with water. The aqueous phase was extracted with further DCM and the combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was combined with the crude material obtained from a second reaction using 5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)phenylacetic acid (Intermediate 97, 0.1 g) under the same conditions described above. The combined crude products were purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-20%, to give (0.740 g) as a white solid.

LCMS (Method A) r/t 2.29 (M+H) 532.

Intermediate 97: 5-Fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-5-ylsulfamoyl)phenylacetic acid

1M Sodium hydroxide solution (5.2 mL) was added to a solution of methyl (1aR,7bS)-5-[4-fluoro-2-(methoxycarbonylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 98, 1.52 g) in methanol (25 mL) and the mixture was stirred and heated at 50° C. for 2 hours. Further 1M sodium hydroxide solution (5.0 mL) was added and stirring was continued for 2 hours at 50° C. After cooling, the mixture was evaporated to dryness and the residue was dissolved in ethyl acetate and water and acidified with concentrated hydrochloric acid. The organic layer was dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo to give 5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)phenylacetic acid (1.51 g) as a white gum.

¹H NMR (CDCl₃): 8.83 (1H, br, s), 7.86 (1H, dd), 7.22 (1H, d), 7.08-6.96 (3H, m), 4.32 (1H, d), 4.00 (2H, d), 3.76 (1H, dd), 3.73 (3H, s), 1.98-1.87 (1H, m), 1.77-1.67 (1H, m), 1.06-0.99 (2H, m).

Intermediate 98: Methyl (1aR,7bS)-5-[4-fluoro-2-(methoxycarbonylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Pyridine (6 mL) was added to a stirred mixture of methyl 2-chlorosulfonyl-5-fluorophenylacetate (Intermediate 99, 1.32 g) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A 1.09 g) in DCM (20 mL) at 0° C. under an atmosphere of nitrogen. The mixture was allowed to warm slowly to room temperature and stirred for 1 hour. The volatiles were removed by evaporation and the residue was partitioned between DCM and 1M hydrochloric acid. The aqueous phase was extracted with DCM and the combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-50%, to give methyl (1aR,7bS)-5-[4-fluoro-2-(methoxycarbonylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (1.57 g) as a gum.

¹H NMR (CDCl₃) δ: 8.77 (1H, br, s), 7.84 (1H, dd), 7.22 (1H, d), 7.09-6.94 (3H, m), 4.33 (1H, d), 4.01 (2H, s), 3.79 (1H, d), 3.76 (3H, s), 3.69 (3H, s), 1.99-1.89 (1H, m), 1.80-1.68 (1H, m), 1.08-0.98 (2H, m).

Intermediate 99: Methyl 2-chlorosulfonyl-5-fluorophenylacetate

Methyl 3-fluorophenylacetate (1.51 g) was added dropwise to chlorosulphonic acid (7 mL) with stirring and ice cooling. The cooling bath was removed and the mixture was allowed to warm to room temperature and left to stand for 16 hours. The mixture was added to a mixture of ice and ethyl acetate and the organic layer was separated, washed with water, dried (MgSO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20%, to give methyl 2-chlorosulfonyl-5-fluorophenylacetate (1.42 g) as a white solid.

¹H NMR (CDCl₃) δ: 8.16 (1H, dd), 7.29-7.16 (2H, m), 4.19 (2H, s), 3.76 (3H, s).

Intermediate 100: (R)-1-Ethylpyrrolidin-3-amine dihydrochloride salt

A solution of tert-butyl (R)-1-ethylpyrrolidin-3-ylcarbamate (Intermediate 101, 0.215 g) in methanol (1 mL) was treated with 4M HCl in dioxane (4 mL) and the mixture was stirred at room temperature for 30 minutes. The volatiles were removed by evaporation to give (R)-1-ethylpyrrolidin-3-amine dihydrochloride salt (0.188 g) as a white gum.

The compound was used without further characterization.

Intermediate 101: tert-Butyl (R)-1-ethylpyrrolidin-3-ylcarbamate

A mixture of tert butyl (R)-pyrrolidin-3-ylcarbamate (5.18 g), bromoethane (2.2 mL) and potassium carbonate (7.68 g) in acetonitrile (100 mL) was stirred at room temperature for 16 hours. Additional bromoethane (0.3 mL) was added and stirring was continued for 2 hours. The volatiles were removed by evaporation and the residue was partitioned between DCM and water. The aqueous phase was extracted with DCM and the combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10%, to give tert-butyl (R)-1-ethylpyrrolidin-3-ylcarbamate (3.62 g) as a colourless oil.

¹H NMR (CDCl₃): 4.93 (1H, br, s), 4.16 (1H, br, s), 2.85-2.75 (1H, m), 2.59-2.53 (2H, br, m), 2.50-2.42 (2H, m), 2.32-2.19 (2H, m), 1.64-1.50 (1H, m), 1.43 (9H, s), 1.10 (3H, t).

Intermediate 102: Methyl (1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A suspension of methyl (1aR,7bS)-5-[2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 103, 0.17 g) in DCM (5 mL) and methanol (2-3 drops) was treated with sodium triacetoxyborohydride (0.2 g) followed by acetaldehyde (0.05 mL). The mixture was stirred at room temperature for 1 hour then poured into water. The organic layers was dried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo. The residue was combined with material from a second reaction starting from methyl (1aR,7bS)-5-[2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.05 g) under the reaction conditions described above. The combined residues were purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-100%, to give methyl (1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.12 g).

LCMS (Method A) r/t 2.20 and 2.33 (M+H) 471.

Intermediate 103: Methyl (1aR,7bS)-5-[2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 78, starting from tert-butyl (R)-3-[2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-5-ylsulfamoyl)benzyl]pyrrolidine-1-carboxylate (Intermediate 104), as a glass.

LCMS (Method E) r/t 2.15 and 2.26 (M+H) 443.

Intermediate 104: tert-Butyl (R)-3-[2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-5-ylsulfamoyl)benzyl]pyrrolidine-1-carboxylate

n-Butyllithium (2.5M in hexanes, 0.75 mL) was added dropwise to a cooled solution of tert-butyl (R)-3-(2-bromobenzyl)pyrrolidine-1-carboxylate (Intermediate 105, 0.6 g) in anhydrous THF (10 mL) under an atmosphere of argon at −78° C. Stirring was continued at −70° C. for 30 minutes then sulfur dioxide was bubbled through the solution for 10 minutes at −78° C. The mixture was stirred at −78° C. for 30 minutes and then allowed to warm slowly to room temperature. The volatiles were removed by evaporation and the residue was dissolved in DCM (20 mL) and cooled to 0° C. The mixture was treated with sulfuryl chloride (0.044 mL) and allowed to warm slowly to room temperature. Stirring was continued for 30 minutes and then the mixture was evaporated to dryness. The residue was dissolved in DCM (10 mL) and pyridine (5 mL) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 0.26 g) were added. The mixture was stirred at room temperature for 2.5 hours and then the volatiles were removed by evaporation. The residue was partitioned between DCM and water and the aqueous phase was extracted with DCM. The combined organic layers were dried (MgSO₄) and filtered and the filtrate was concentrated in vacuo. The reaction was repeated twice using tert-butyl (R)-3-(2-bromobenzyl)pyrrolidine-1-carboxylate (0.598 g and 0.252 g respectively) under the reaction conditions described above. The residues from the three reactions were combined and purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-30% to give tert-butyl (R)-3-[2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-5-ylsulfamoyl)benzyl]-pyrrolidine-1-carboxylate (0.23 g) as a glass.

¹H NMR (CDCl₃) δ: 8.99 (1H, d), 7.88 (1H, d), 7.49-7.38 (1H, m), 7.30-7.18 (2H, m), 7.07-6.99 (1H, m), 4.31 (1H, d), 3.80-3.70 (4H, m), 3.53-3.36 (2H, m), 3.26-3.14 (1H, m), 3.11-2.92 (2H, m), 2.91-2.73 (1H, m), 2.58-2.43 (1H, m), 1.98-1.82 (2H, m), 1.74-1.54 (2H, m), 1.44 (9H, s), 1.05-0.95 (2H, m).

Intermediate 105: tert-Butyl (R)-3-(2-bromobenzyl)pyrrolidine-1-carboxylate

Prepared by proceeding in a similar manner to Intermediate 25, starting from tert-butyl (R)-3-iodomethylpyrrolidine-1-carboxylate (Intermediate 26) and 2-bromobenzeneboronic acid as an oil.

¹H NMR (CDCl₃) δ: 7.54 (1H, t), 7.25-7.15 (2H, m), 7.12-7.03 (1H, m), 3.59-3.38 (2H, m), 3.34-3.16 (1H, m), 3.09-2.98 (1H, m), 2.89-2.73 (2H, m), 2.60-2.47 (1H, m), 1.98-1.84 (1H, m), 1.68-1.56 (1H, m), 1.45 (9H, s).

Intermediate 106: Methyl (1aR,7bS)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]-methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of (S)-1-ethylpyrrolidine-3-carboxylic acid (Intermediate 111, 0.089 g) and HOBT (0.084 g) in DCM (10 mL) was treated with EDAC (0.114 g) and the mixture was stirred for 10 minutes. Methyl (1aR,7bS)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 107, 0.25 g) was then added and stirring was continued at room temperature for 3 days. The mixture was washed with water and the organic layer was dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-15%, to give methyl (1aR,7bS)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]-methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.207 g) as a white solid.

LCMS (Method E) r/t 2.27 (M+H) 532.

Intermediate 107: Methyl (1aR,7bS)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of potassium carbonate (1.61 g) in water (10 mL) was added to a solution of methyl (1aR,7bS)-5-[4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 108, 1.17 g) in methanol (40 mL) and the resultant mixture was stirred and heated at 45° C. for 2 hours. After cooling, the mixture was concentrated in vacuo and the residue was partitioned between water and DCM. The organic layer was washed with brine, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to give methyl (1aR,7bS)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.767 g) as a white solid.

LCMS (Method E) r/t 2.05 (M+H) 407.

Intermediate 108: Methyl (1aR,7bS)-5-[4-fluoro-2-(trifluoroacetylaminomethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 0.972 g) was added to a solution of 4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonyl chloride (Intermediate 109, 1.53 g) in DCM (25 mL) and pyridine (6 mL). The mixture was stirred at room temperature for 18 hours. The volatiles were removed by evaporation and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-40%, to give methyl (1aR,7bS)-5-[4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (1.17 g) as a white solid.

LCMS (Method E) r/t 3.70 (M−H) 501.

Intermediate 109: 4-Fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonyl chloride

3-Fluoro-N-trifluoroacetylbenzylamine (Intermediate 110, 1.11 g) was added portionwise to chlorosulfonic acid (5 mL), while stirring and cooling in an ice bath. On completion of the addition, the ice bath was removed and the mixture was allowed to warm to room temperature then heated at 70° C. for 3 hours. After cooling, the mixture was added slowly to ice and the resultant suspension was extracted with ethyl acetate, washed with water, dried (MgSO₄) and filtered. The filtrate was evaporated to dryness to give 4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonyl chloride (1.53 g) as a brown solid.

¹H NMR (CDCl₃): 8.18 (1H, dd), 7.47 (1H, dd), 7.31-7.21 (1H, m), 7.18 (1H, br s), 4.92 (2H, d).

Intermediate 110: 3-Fluoro-N-trifluoroacetylbenzylamine

Trifluoroacetic anhydride (5.05 g) was added dropwise to an ice-cooled solution of 3-fluorobenzylamine (2.5 g) and triethylamine (2.22 g) in ethyl acetate (75 mL) while maintaining the temperature below 10° C. The mixture was stirred at 0-5° C. for 1 hour then allowed to warm to room temperature and stirred for 2 hours. Water was added and the layers were separated. The organic layer was washed with water, dried (MgSO₄) and filtered. The filtrate was evaporated to dryness to give 3-fluoro-N-trifluoroacetylbenzylamine (4.58 g) as an oil which crystallised on standing to a white solid.

¹H NMR (CDCl₃): 7.41-7.27 (1H, m), 7.13-6.92 (3H, m), 6.72 (1H, br s), 4.53 (2H, d).

Intermediate 111: (S)-1-Ethylpyrrolidine-3-carboxylic acid

A mixture of benzyl (S)-1-ethylpyrrolidine-3-carboxylate (Intermediate 112, 0.563 g), 20% palladium hydroxide on carbon (0.056 g), ethyl acetate (9 mL) and IMS (1 mL) was degassed and stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered through Celite, washing the pad with ethyl acetate and the filtrate was concentrated in vacuo to give (S)-1-ethylpyrrolidine-3-carboxylic acid (0.318 g) as a solid.

¹H NMR (CDCl₃) δ: 12.46-10.55 (1H, br s), 3.84-3.57 (1H, br s), 3.49-3.26 (1H, br s), 3.26-2.93 (5H, m), 2.50-2.33 (1H, m), 2.28-2.11 (1H, m), 1.35 (3H, t).

Intermediate 112: Benzyl (S)-1-ethylpyrrolidine-3-carboxylate

Ethyl bromide (0.785 mL) was added to a mixture of benzyl (S)-pyrrolidine-3-carboxylate hydrochloride salt (Intermediate 113, 2.53 g) and potassium carbonate (3.62 g) in DMF (50 mL) at room temperature and the mixture was stirred for 3 days. The mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with brine, dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in cyclohexane and filtered through a PTFE membrane. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and ethyl acetate, with a gradient of 0-10%, to give benzyl (S)-1-ethylpyrrolidine-3-carboxylate (1.06 g).

LCMS (Method E) r/t 1.50 (M+H) 234.

Intermediate 113: Benzyl (S)-pyrrolidine-3-carboxylate hydrochloride salt

A solution of 3-benzyl 1-tert-butyl (S)-pyrrolidine-1,3-dicarboxylate (Intermediate 114, 3.2 g) in DCM (25 mL) was treated with HCl (4M in dioxane) and the mixture was stirred at room temperature for 18 hours. The volatiles were removed by evaporation to give benzyl (S)-pyrrolidine-3-carboxylate hydrochloride salt as a sticky solid.

LCMS (Method E) r/t 1.46 (M) 206.

Intermediate 114: 3-Benzyl 1-tert-butyl (S)-pyrrolidine-1,3-dicarboxylate

DBU (0.764 mL) was added to a mixture of benzyl bromide (0.61 mL), (S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (1 g) in anhydrous toluene (10 mL) and the mixture was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-35%, to give 3-benzyl 1-tert-butyl (S)-pyrrolidine-1,3-dicarboxylate (0.859 g).

¹H NMR (CDCl₃) δ: 7.39-7.29 (5H, m), 5.14 (2H, s), 3.70-3.41 (3H, m), 3.41-3.27 (1H, m), 3.08 (1H, m), 2.13 (2H, q), 1.45 (9H, s).

Intermediate 115: Methyl (1aR,7bS)-5-(2-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoro-acetylamino]ethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Pyridine (1 mL) was added to a stirred, cooled solution of 2-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-4-fluorobenzenesulfonyl chloride (Intermediate 116, 0.433 g) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 0.22 g) in DCM (10 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2.5 hours. Further methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8A, 0.08 g) was added and stirring was continued for 1 hour. The mixture was partitioned between saturated aqueous sodium bicarbonate and DCM and the aqueous layer was extracted with further DCM. The combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and ethyl acetate, with a gradient of 0-20% to give methyl (1aR,7bS)-5-(2-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoro-acetylamino]ethyl}-4-fluorobenzene-sulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.048 g) as a gum.

LCMS (Method A) r/t 2.63 (M+H) 614.

Intermediate 116: 2-{2-[N—((R)-1-Ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-4-fluorobenzenesulfonyl chloride

Chlorosulfonic acid (1.1 mL) was added slowly to a cooled solution of 1-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-3-fluorobenzene (Intermediate 117, 0.54 g) in DCM (2 mL) in an ice bath. On completion of the addition, the mixture was allowed to warm slowly to room temperature and stirred for 30 minutes. The mixture was poured into ice and extracted with DCM, dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness to give 2-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-4-fluorobenzenesulfonyl chloride (0.048 g) as a white solid.

LCMS (Method B) r/t 2.32 (M+H) 431.

Intermediate 117: 1-{2-[N—((R)-1-Ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-3-fluorobenzene

Trifluoroacetic anhydride (0.43 mL) was added to a cooled solution of ((R)-1-ethylpyrrolidin-3-yl)-[2-(3-fluorophenyl)ethyl]amine (Intermediate 118, 0.58 g) and triethylamine (1.03 mL) in DCM (20 mL) in an ice bath. On completion of the addition the mixture was allowed to warm to room temperature and stirred for 2 hours. Further trifluoroacetic anhydride (0.1 mL) was added and stirring was continued for 30 minutes. The mixture was partitioned between saturated aqueous sodium bicarbonate and DCM and the aqueous layer was extracted with DCM. The combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-10%, to give 1-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-3-fluorobenzene (0.55 g) as a gum.

¹H NMR (CDCl₃) δ: 7.32-7.21 (1H, m), 7.06-6.87 (3H, m), 4.69-4.49 (1H, m), 3.68 (2H, t), 3007-2.82 (3H, m), 2.72-2.63 (1H, m), 2.58-2.32 (3H, m), 2.28-2.14 (2H, m), 1.81-1.67 (1H, m), 1.10 (3H, t).

Intermediate 118: ((R)-1-Ethylpyrrolidin-3-yl)-[2-(3-fluorophenyl)ethyl]amine

A mixture of 1-methanesulfonyloxy-2-(3-fluorophenyl)ethane (Intermediate 119, 0.74 g), (R)-1-ethylpyrrolidin-3-amine dihydrochloride salt (Intermediate 100, 0.64 g) and potassium carbonate (2.36 g) in acetonitrile (15 mL) was stirred and heated in a sealed vial at 80° C. overnight. The reaction was repeated twice, using 1-methanesulfonyloxy-2-(3-fluorophenyl)ethane (Intermediate 119, 0.74 g and 0.31 g respectively) under the reaction conditions described above. The combined crude reaction mixtures were partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM with a gradient of 0-20%, to give ((R)-1-ethylpyrrolidin-3-yl)-[2-(3-fluorophenyl)ethyl]amine (0.59 g) as a gum.

¹H NMR (CDCl₃) δ: 7.28-7.20 (1H, m), 7.01-6.85 (3H, m), 3.36-3.27 (1H, m), 2.88-2.75 (4H, m), 2.75-2.68 (1H, m), 2.64-2.55 (1H, m), 2.53-2.2.39 (3H, m), 2.36-2.29 (1H, m), 2.18-2.06 (1H, m), 1.57-1.46 (1H, m), 1.09 (3H, t).

Intermediate 119: 1-Methanesulfonyloxy-2-(3-fluorophenyl)ethane

Methanesulfonyl chloride (0.92 mL) was added to a stirred, cooled solution of 2-(3-fluorophenyl)ethanol (1.28 g) and triethylamine (2 mL) in DCM (15 mL) at 0° C. under an atmosphere of nitrogen. On completion of the addition, the mixture was stirred at 0° C. for 30 minutes then at room temperature for 1.5 hours. The mixture was partitioned between DCM and 1M hydrochloric acid and the aqueous layer was extracted with DCM. The combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-100% to give 1-methanesulfonyloxy-2-(3-fluorophenyl)ethane (1.92 g) as a colourless oil.

¹H NMR (CDCl₃) δ: 7.33-7.26 (1H, m), 7.05-6.92 (3H, m), 4.42 (2H, t), 3.06 (2H, t), 2.89 (3H, s).

Biological Example

Compounds are tested for their capacity to inhibit recombinant human MetAP2 activity using the following assay.

Human recombinant MetAP2 expressed in Sf9 cells followed by affinity purification and EDTA treatment to remove endogenous active site cation was dialysed against MnCl₂ to produce the manganese enzyme used in the assay. The assay was carried out for 30 minutes at 25° C. in 50 mM HEPES buffer containing 100 mM NaCl, pH 7.5 the presence of 0.75 mM Methionine-Alanine-Serine (MAS) substrate and 50 μg/ml amino acid oxidase using a dilution of purified MetAP2 giving >3-fold signal:noise. Cleavage of the substrate by MetAP2 and oxidation of free methionine by amino acid oxidase was detected and quantified using fluorescence generated by Amplex red (10-acetyl-3,7-dihydroxyphenoxazine) in combination with horseradish peroxidase which detects H₂O₂ released during the oxidation step. The fluorescent signal was detected using a multiwell fluorimeter. Compounds were diluted in DMSO prior to addition to assay buffer, the final DMSO concentration in the assay being 1%.

The IC₅₀ is defined as the concentration at which a given compound achieves 50% inhibition of control. IC₅₀ values are calculated using the XLfit software package (version 2.0.5).

Compounds of the invention demonstrated activity in the assay of this Example as indicated in the following table, wherein A represents <0.05 μM, B represents IC₅₀ between 0.05 μM and 0.5 μM, and C represents IC₅₀>0.5 μM.

Ac- Compound name tivity (1aR,7bS)-5-[2-(2-Diethylaminomethylcyclopropyl)-4-fluoro- B benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid First eluting enantiomer of (1aR,7bS)-5-[2-(2-diethylamino- A methylcyclopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid Second eluting enantiomer of (1aR,7bS)-5-[2-(2-diethylamino- B methylcyclopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-{4-Fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]- B benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid (1aR,7bS)-5-[2-(3-Diethylamino-2,2-dimethylpropyl)-4- A fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopro- [c]chromene-4-carboxylic acid (1aR,7bS)-5-[4-Fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene- A sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4- carboxylic acid (1aR,7bS)-5-[4-Fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzene- A sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4- carboxylic acid (1aR,7bS)-5-{4-Fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)- A pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-[2-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluoro- A benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid (1aR,7bS)-5-[2-((Z)-1-Azabicyclo[2.2.2]oct-3-ylidenemethyl)-4- A fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid (1aR,7bS)-5-[2-((E)-1-Azabicyclo[2.2.2]oct-3-ylidenemethyl)-4- A fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid (1aR,7bS)-5-{2-[(E)-(1-Ethylpiperidin-3-ylidene)methyl]-4- A fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid (1aR,7bS)-5-{2-[(Z)-(1-Ethylpiperidin-3-ylidene)methyl]-4- B fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid First eluting enantiomer of (1aR,7bS)-5-[2-(1-ethylpiperidin-3- A ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid Second eluting enantiomer of (1aR,7bS)-5-[2-(1-ethylpiperidin-3- A ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-{2-[2-((S)-1-Ethylpyrrolidin-2-yl)ethyl]-4-fluoro- A benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid (1aR,7bS)-5-{4-Fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3- A ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-[2-((Endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3- A yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-[2-((Exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3- A yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin- A 1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5{4-Fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1- B enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid (1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1- B yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-[2-(3-Ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluoro- B benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid (1aR,7bS)-5-{4-Fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]- A benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid (1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-((S)-3-hydroxymethylpyrrolidin- A 1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin- A 1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-(4-Fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2- A yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-(4-Fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2- A yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-[4-Fluoro-2-(hexahydro-1H-pyrrolizin-2- A ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-{2-[((S)-1-Ethylpyrrolidin-3-ylcarbamoyl)methyl]- A 4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid (1aR,7bS)-5-[2-((3R)-1-Ethylpyrrolidin-3-ylmethyl)benzene- A sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4- carboxylic acid (1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)amino- A methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid - formic acid (1:1) (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4- A fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid - formic acid (1:1)

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. 

What is claimed is:
 1. A compound selected from the group consisting of: (1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, or enantiomers thereof; (1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopro-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[4-fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)-pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((Z)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((E)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[(E)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[(Z)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, or enantiomers thereof; (1aR,7bS)-5-[2-((R)-1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((S)-1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aR,7bS)-5-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aR,7bS)-5{4-fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{4-fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-(4-fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-(4-fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((3R)-1-ethylpyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)amino-methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid-formic acid (1:1); (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid formic acid (1:1) and pharmaceutically acceptable salts, stereoisomers, esters and prodrugs thereof.
 2. A pharmaceutically acceptable composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
 3. The composition of claim 2, wherein the composition is formulated as a unit dose.
 4. The composition of claim 2, wherein the composition is formulated for oral administration.
 5. The composition of claim 2, wherein the composition is formulated for intravenous or subcutaneous administration. 